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<!DOCTYPE html> <html lang="en" class="grade-c"> <head> <title>Human genetic basis of coronavirus disease 2019 | Signal Transduction and Targeted Therapy</title> <link rel="alternate" type="application/rss+xml" href="https://www.nature.com/sigtrans.rss"/> <link rel="preconnect" href="https://cmp.nature.com" crossorigin> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width,initial-scale=1.0,maximum-scale=5,user-scalable=yes"> <meta name="360-site-verification" content="5a2dc4ab3fcb9b0393241ffbbb490480" /> <script data-test="dataLayer"> window.dataLayer = [{"content":{"category":{"contentType":"review article","legacy":{"webtrendsPrimaryArticleType":"reviews","webtrendsSubjectTerms":"infectious-diseases;medical-genetics;predictive-markers","webtrendsContentCategory":null,"webtrendsContentCollection":null,"webtrendsContentGroup":"Signal Transduction and Targeted 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Oswaldo Cruz; citation_title=Genomic and phylogenetic characterisation of an imported case of SARS-CoV-2 in Amazonas State, Brazil; citation_author=VAD Nascimento; citation_volume=115; citation_publication_date=2020; citation_pages=e200310; citation_doi=10.1590/0074-02760200310; citation_id=CR19"/> <meta name="citation_reference" content="citation_journal_title=Stem Cell Rep.; citation_title=Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection; citation_author=K Dobrindt; citation_volume=16; citation_publication_date=2021; citation_pages=505-518; citation_doi=10.1016/j.stemcr.2021.02.010; citation_id=CR20"/> <meta name="citation_reference" content="citation_journal_title=Travel Med. Infect. 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Pathog.; citation_title=Clinical characteristics, laboratory findings, radiographic signs and outcomes of 61,742 patients with confirmed COVID-19 infection: a systematic review and meta-analysis; citation_author=A Pormohammad; citation_volume=147; citation_publication_date=2020; citation_pages=104390; citation_doi=10.1016/j.micpath.2020.104390; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=Lancet; citation_title=A novel coronavirus outbreak of global health concern; citation_author=C Wang, PW Horby, FG Hayden, GF Gao; citation_volume=395; citation_publication_date=2020; citation_pages=470-473; citation_doi=10.1016/S0140-6736(20)30185-9; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=Immunity; citation_title=Plasma proteomics identify biomarkers and pathogenesis of COVID-19; citation_author=T Shu; citation_volume=53; citation_publication_date=2020; citation_pages=1108-1122.e5; citation_doi=10.1016/j.immuni.2020.10.008; citation_id=CR24"/> <meta name="citation_reference" content="citation_journal_title=J. Infect.; citation_title=Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis; citation_author=L Fu; citation_volume=80; citation_publication_date=2020; citation_pages=656-665; citation_doi=10.1016/j.jinf.2020.03.041; citation_id=CR25"/> <meta name="citation_reference" content="citation_journal_title=Sci. Rep.; citation_title=Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis; citation_author=CKH Wong, JYH Wong, EHM Tang, CH Au, AKC Wai; citation_volume=10; citation_publication_date=2020; citation_doi=10.1038/s41598-020-74988-9; citation_id=CR26"/> <meta name="citation_reference" content="citation_journal_title=Int. J. Infect. Dis.; citation_title=Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis; citation_author=J Yang; citation_volume=94; citation_publication_date=2020; citation_pages=91-95; citation_doi=10.1016/j.ijid.2020.03.017; citation_id=CR27"/> <meta name="citation_reference" content="citation_journal_title=J. Med. Virol.; citation_title=COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis; citation_author=LQ Li; citation_volume=92; citation_publication_date=2020; citation_pages=577-583; citation_doi=10.1002/jmv.25757; citation_id=CR28"/> <meta name="citation_reference" content="citation_journal_title=Int. J. Environ. Res. Public Health; citation_title=Correlations of clinical and laboratory characteristics of COVID-19: a systematic review and meta-analysis; citation_author=RA Ghayda; citation_volume=17; citation_publication_date=2020; citation_pages=5026; citation_doi=10.3390/ijerph17145026; citation_id=CR29"/> <meta name="citation_reference" content="citation_journal_title=Brain Inj.; citation_title=Neurological manifestations in COVID-19: a systematic review and meta-analysis; citation_author=TH Chua, Z Xu, NKK King; citation_volume=34; citation_publication_date=2020; citation_pages=1549-1568; citation_doi=10.1080/02699052.2020.1831606; citation_id=CR30"/> <meta name="citation_reference" content="citation_journal_title=J. Neurol. Sci.; citation_title=Parkinson’s disease after COVID-19; citation_author=K Makhoul, J Jankovic; citation_volume=422; citation_publication_date=2021; citation_pages=117331; citation_doi=10.1016/j.jns.2021.117331; citation_id=CR31"/> <meta name="citation_reference" content="citation_journal_title=Indian J. Pediatr.; citation_title=A review of coronavirus disease-2019 (COVID-19); citation_author=T Singhal; citation_volume=87; citation_publication_date=2020; citation_pages=281-286; citation_doi=10.1007/s12098-020-03263-6; citation_id=CR32"/> <meta name="citation_reference" content="citation_journal_title=Trends Immunol.; citation_title=Mechanisms of SARS-CoV-2 transmission and pathogenesis; citation_author=AG Harrison, T Lin, P Wang; citation_volume=41; citation_publication_date=2020; citation_pages=1100-1115; citation_doi=10.1016/j.it.2020.10.004; citation_id=CR33"/> <meta name="citation_reference" content="citation_journal_title=Front. Pharm.; citation_title=COVID-19 outbreak: pathogenesis, current therapies, and potentials for future management; citation_author=MF Hossain; citation_volume=11; citation_publication_date=2020; citation_pages=563478; citation_doi=10.3389/fphar.2020.563478; citation_id=CR34"/> <meta name="citation_reference" content="citation_journal_title=Cell Stem Cell; citation_title=Modeling multi-organ infection by SARS-CoV-2 using stem cell technology; citation_author=CR Simoneau, M Ott; citation_volume=27; citation_publication_date=2020; citation_pages=859-868; citation_doi=10.1016/j.stem.2020.11.012; citation_id=CR35"/> <meta name="citation_reference" content="citation_journal_title=Gerontology; citation_title=The clinical characteristics and risk factors of severe COVID-19; citation_author=J Hu, Y Wang; citation_volume=6; citation_publication_date=2021; citation_pages=1-12; citation_id=CR36"/> <meta name="citation_reference" content="citation_journal_title=Int. J. Infect. Dis.; citation_title=Asymptomatic patients as a source of COVID-19 infections: a systematic review and meta-analysis; citation_author=A Kronbichler; citation_volume=98; citation_publication_date=2020; citation_pages=180-186; citation_doi=10.1016/j.ijid.2020.06.052; citation_id=CR37"/> <meta name="citation_reference" content="citation_journal_title=Acad. Radiol.; citation_title=CT manifestations and clinical characteristics of 1115 patients with coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis; citation_author=S Wan; citation_volume=27; citation_publication_date=2020; citation_pages=910-921; citation_doi=10.1016/j.acra.2020.04.033; citation_id=CR38"/> <meta name="citation_reference" content="citation_journal_title=Virol. J.; citation_title=The chest CT features of coronavirus disease 2019 (COVID-19) in China: a meta-analysis of 19 retrospective studies; citation_author=H Yang, Y Lan, X Yao, S Lin, B Xie; citation_volume=17; citation_publication_date=2020; citation_pages=159; citation_doi=10.1186/s12985-020-01432-9; citation_id=CR39"/> <meta name="citation_reference" content="citation_journal_title=Infez. Med.; citation_title=Chest computed tomography findings in hospitalized COVID-19 patients: a systematic review and meta-analysis; citation_author=SZ Muhammad; citation_volume=28; citation_publication_date=2020; citation_pages=295-301; citation_id=CR40"/> <meta name="citation_reference" content="citation_journal_title=Nature; citation_title=A new coronavirus associated with human respiratory disease in China; citation_author=F Wu; citation_volume=579; citation_publication_date=2020; citation_pages=265-269; citation_doi=10.1038/s41586-020-2008-3; citation_id=CR41"/> <meta name="citation_reference" content="citation_journal_title=Lancet; citation_title=Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China; citation_author=C Huang; citation_volume=395; citation_publication_date=2020; citation_pages=497-506; citation_doi=10.1016/S0140-6736(20)30183-5; citation_id=CR42"/> <meta name="citation_reference" content="citation_journal_title=Biol. Proced. Online; citation_title=Effects of cell proteostasis network on the survival of SARS-CoV-2; citation_author=F Khomari, M Nabi-Afjadi, S Yarahmadi, H Eskandari, E Bahreini; citation_volume=23; citation_publication_date=2021; citation_pages=8; citation_doi=10.1186/s12575-021-00145-9; citation_id=CR43"/> <meta name="citation_reference" content="citation_journal_title=Nat. Rev. Microbiol.; citation_title=Coronavirus biology and replication: implications for SARS-CoV-2; citation_author=P V’kovski, A Kratzel, S Steiner, H Stalder, V Thiel; citation_volume=19; citation_publication_date=2021; citation_pages=155-170; citation_doi=10.1038/s41579-020-00468-6; citation_id=CR44"/> <meta name="citation_reference" content="citation_journal_title=Int. J. Mol. Sci.; citation_title=Structural and evolutionary analysis indicate that the SARS-CoV-2 Mpro is a challenging target for small-molecule inhibitor design; citation_author=M Bzówka; citation_volume=21; citation_publication_date=2020; citation_pages=3099; citation_doi=10.3390/ijms21093099; citation_id=CR45"/> <meta name="citation_reference" content="citation_journal_title=Infect. Dis. Poverty; citation_title=A close look at the biology of SARS-CoV-2, and the potential influence of weather conditions and seasons on COVID-19 case spread; citation_author=KA Adedokun, AO Olarinmoye, JO Mustapha, RT Kamorudeen; citation_volume=9; citation_publication_date=2020; citation_pages=77; citation_doi=10.1186/s40249-020-00688-1; citation_id=CR46"/> <meta name="citation_reference" content="citation_journal_title=Emerg. Microbes Infect.; citation_title=RNA based mNGS approach identifies a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan outbreak; citation_author=L Chen; citation_volume=9; citation_publication_date=2020; citation_pages=313-319; citation_doi=10.1080/22221751.2020.1725399; citation_id=CR47"/> <meta name="citation_reference" content="citation_journal_title=Nature; citation_title=A pneumonia outbreak associated with a new coronavirus of probable bat origin; citation_author=P Zhou; citation_volume=579; citation_publication_date=2020; citation_pages=270-273; citation_doi=10.1038/s41586-020-2012-7; citation_id=CR48"/> <meta name="citation_reference" content="citation_journal_title=J. Adv. Res.; citation_title=COVID-19 infection: origin, transmission, and characteristics of human coronaviruses; citation_author=MA Shereen, S Khan, A Kazmi, N Bashir, R Siddique; citation_volume=24; citation_publication_date=2020; citation_pages=91-98; citation_doi=10.1016/j.jare.2020.03.005; citation_id=CR49"/> <meta name="citation_reference" content="citation_journal_title=Clin. Infect. Dis.; citation_title=It is time to address airborne transmission of coronavirus disease 2019 (COVID-19); citation_author=L Morawska, DK Milton; citation_volume=71; citation_publication_date=2020; citation_pages=2311-2313; citation_id=CR50"/> <meta name="citation_reference" content="citation_journal_title=Mil. Med. Res.; citation_title=A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version); citation_author=YH Jin; citation_volume=7; citation_publication_date=2020; citation_pages=4; citation_id=CR51"/> <meta name="citation_reference" content="citation_journal_title=Biochem. Soc. Trans.; citation_title=Transmission and prevention of SARS-CoV-2; citation_author=Z Wang; citation_volume=48; citation_publication_date=2020; citation_pages=2307-2316; citation_doi=10.1042/BST20200693; citation_id=CR52"/> <meta name="citation_reference" content="citation_journal_title=Nat. Commun.; citation_title=Transplacental transmission of SARS-CoV-2 infection; citation_author=AJ Vivanti; citation_volume=11; citation_publication_date=2020; citation_doi=10.1038/s41467-020-17436-6; citation_id=CR53"/> <meta name="citation_reference" content="citation_journal_title=Front. Immunol.; citation_title=SARS-CoV-2: pathogenesis, and advancements in diagnostics and treatment; citation_author=K Khalaf; citation_volume=11; citation_publication_date=2020; citation_pages=570927; citation_doi=10.3389/fimmu.2020.570927; citation_id=CR54"/> <meta name="citation_reference" content="citation_journal_title=Environ. Int.; citation_title=Airborne transmission of SARS-CoV-2: the world should face the reality; citation_author=L Morawska, J Cao; citation_volume=139; citation_publication_date=2020; citation_pages=105730; citation_doi=10.1016/j.envint.2020.105730; citation_id=CR55"/> <meta name="citation_reference" content="citation_journal_title=JAMA; citation_title=Presumed asymptomatic carrier transmission of COVID-19; citation_author=Y Bai; citation_volume=323; citation_publication_date=2020; citation_pages=1406-1407; citation_doi=10.1001/jama.2020.2565; citation_id=CR56"/> <meta name="citation_reference" content="Frampton, D. et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. Lancet Infect. Dis. 21, 1246–1256 (2021)."/> <meta name="citation_reference" content="citation_journal_title=Viruses; citation_title=Inferring the association between the risk of COVID-19 case fatality and N501Y substitution in SARS-CoV-2; citation_author=S Zhao; citation_volume=13; citation_publication_date=2021; citation_pages=638; citation_doi=10.3390/v13040638; citation_id=CR58"/> <meta name="citation_reference" content="citation_journal_title=MMWR Morb. Mortal. Wkly. Rep.; citation_title=Emergence of SARS-CoV-2 B.1.1.7 lineage-United States, December 29, 2020-January 12, 2021; citation_author=SE Galloway; citation_volume=70; citation_publication_date=2021; citation_pages=95-99; citation_doi=10.15585/mmwr.mm7003e2; citation_id=CR59"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Structural and functional basis of SARS-CoV-2 entry by using human ACE2; citation_author=Q Wang; citation_volume=181; citation_publication_date=2020; citation_pages=894-904.e9; citation_doi=10.1016/j.cell.2020.03.045; citation_id=CR60"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor; citation_author=M Hoffmann; citation_volume=181; citation_publication_date=2020; citation_pages=271-280.e8; citation_doi=10.1016/j.cell.2020.02.052; citation_id=CR61"/> <meta name="citation_reference" content="citation_journal_title=Science; citation_title=Structure of SARS coronavirus spike receptor-binding domain complexed with receptor; citation_author=F Li, W Li, M Farzan, SC Harrison; citation_volume=309; citation_publication_date=2005; citation_pages=1864-1868; citation_doi=10.1126/science.1116480; citation_id=CR62"/> <meta name="citation_reference" content="citation_journal_title=Front. Immunol.; citation_title=ACE2/ADAM17/TMPRSS2 interplay may be the main risk factor for COVID-19; citation_author=D Zipeto, JDF Palmeira, GA Argañaraz, ER Argañaraz; citation_volume=11; citation_publication_date=2020; citation_pages=576745; citation_doi=10.3389/fimmu.2020.576745; citation_id=CR63"/> <meta name="citation_reference" content="citation_journal_title=Front. Genet.; citation_title=Host genetic variants potentially associated with SARS-CoV-2: a multi-population analysis; citation_author=MK Smatti, YA Al-Sarraj, O Albagha, HM Yassine; citation_volume=11; citation_publication_date=2020; citation_pages=578523; citation_doi=10.3389/fgene.2020.578523; citation_id=CR64"/> <meta name="citation_reference" content="citation_journal_title=Med. Drug Discov.; citation_title=Cyclophilin A and CD147: novel therapeutic targets for the treatment of COVID-19; citation_author=C Liu, A Brunn, D Zhu; citation_volume=7; citation_publication_date=2020; citation_pages=100056; citation_doi=10.1016/j.medidd.2020.100056; citation_id=CR65"/> <meta name="citation_reference" content="citation_journal_title=Cell Res.; citation_title=AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells; citation_author=S Wang; citation_volume=31; citation_publication_date=2021; citation_pages=126-140; citation_doi=10.1038/s41422-020-00460-y; citation_id=CR66"/> <meta name="citation_reference" content="citation_journal_title=J. Infect.; citation_title=COVID-19 spike-host cell receptor GRP78 binding site prediction; citation_author=IM Ibrahim, DH Abdelmalek, ME Elshahat, AA Elfiky; citation_volume=80; citation_publication_date=2020; citation_pages=554-562; citation_doi=10.1016/j.jinf.2020.02.026; citation_id=CR67"/> <meta name="citation_reference" content="citation_journal_title=Emerg. Microbes Infect.; citation_title=Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26; citation_author=N Vankadari, JA Wilce; citation_volume=9; citation_publication_date=2020; citation_pages=601-604; citation_doi=10.1080/22221751.2020.1739565; citation_id=CR68"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Identification of required host factors for SARS-CoV-2 infection in human cells; citation_author=Z Daniloski; citation_volume=184; citation_publication_date=2021; citation_pages=92-105.e16; citation_doi=10.1016/j.cell.2020.10.030; citation_id=CR69"/> <meta name="citation_reference" content="citation_journal_title=Genes; citation_title=COVID-19 and genetic variants of protein involved in the SARS-CoV-2 entry into the host cells; citation_author=A Latini; citation_volume=11; citation_publication_date=2020; citation_pages=1010; citation_doi=10.3390/genes11091010; citation_id=CR70"/> <meta name="citation_reference" content="citation_journal_title=Biophys. J.; citation_title=Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of spike protein domains S1 and S2; citation_author=ZL Li, M Buck; citation_volume=120; citation_publication_date=2021; citation_pages=2828-2837; citation_doi=10.1016/j.bpj.2021.05.026; citation_id=CR71"/> <meta name="citation_reference" content="citation_journal_title=Eur. J. Intern. Med.; citation_title=The pivotal link between ACE2 deficiency and SARS-CoV-2 infection; citation_author=P Verdecchia, C Cavallini, A Spanevello, F Angeli; citation_volume=76; citation_publication_date=2020; citation_pages=14-20; citation_doi=10.1016/j.ejim.2020.04.037; citation_id=CR72"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Respir. Cell Mol. Biol.; citation_title=Pulmonary endothelial dysfunction and thrombotic complications in COVID-19 patients; citation_author=C Rodríguez; citation_volume=64; citation_publication_date=2020; citation_pages=407-415; citation_doi=10.1165/rcmb.2020-0359PS; citation_id=CR73"/> <meta name="citation_reference" content="citation_journal_title=N. Engl. J. Med.; citation_title=Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19; citation_author=M Vaduganathan; citation_volume=382; citation_publication_date=2020; citation_pages=1653-1659; citation_doi=10.1056/NEJMsr2005760; citation_id=CR74"/> <meta name="citation_reference" content="citation_journal_title=Cell Biosci.; citation_title=ACE2: the molecular doorway to SARS-CoV-2; citation_author=MM Medina-Enríquez; citation_volume=10; citation_publication_date=2020; citation_pages=148; citation_doi=10.1186/s13578-020-00519-8; citation_id=CR75"/> <meta name="citation_reference" content="citation_journal_title=Cell Mol. Life Sci.; citation_title=Angiotensin-converting enzyme-2: a molecular and cellular perspective; citation_author=FJ Warner, AI Smith, NM Hooper, AJ Turner; citation_volume=61; citation_publication_date=2004; citation_pages=2704-2713; citation_doi=10.1007/s00018-004-4240-7; citation_id=CR76"/> <meta name="citation_reference" content="citation_journal_title=J. Mol. Med.; citation_title=Update on tissue renin-angiotensin systems; citation_author=M Bader, D Ganten; citation_volume=86; citation_publication_date=2008; citation_pages=615-621; citation_doi=10.1007/s00109-008-0336-0; citation_id=CR77"/> <meta name="citation_reference" content="citation_journal_title=Circ. Res.; citation_title=A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9; citation_author=M Donoghue; citation_volume=87; citation_publication_date=2000; citation_pages=e1-e9; citation_doi=10.1161/01.RES.87.5.e1; citation_id=CR78"/> <meta name="citation_reference" content="citation_journal_title=Circ. Res.; citation_title=Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure; citation_author=VB Patel, JC Zhong, MB Grant, GY Oudit; citation_volume=118; citation_publication_date=2016; citation_pages=1313-1326; citation_doi=10.1161/CIRCRESAHA.116.307708; citation_id=CR79"/> <meta name="citation_reference" content="citation_journal_title=Clin. Inter. Aging; citation_title=COVID-19: the influence of ACE genotype and ACE-I and ARBs on the course of SARS-CoV-2 infection in elderly patients; citation_author=J Sieńko; citation_volume=15; citation_publication_date=2020; citation_pages=1231-1240; citation_doi=10.2147/CIA.S261516; citation_id=CR80"/> <meta name="citation_reference" content="citation_journal_title=J. Pathol.; citation_title=The emerging role of ACE2 in physiology and disease; citation_author=I Hamming; citation_volume=212; citation_publication_date=2007; citation_pages=1-11; citation_doi=10.1002/path.2162; citation_id=CR81"/> <meta name="citation_reference" content="citation_journal_title=Mayo Clin. Proc.; citation_title=COVID-19 and sex differences: mechanisms and biomarkers; citation_author=T Haitao; citation_volume=95; citation_publication_date=2020; citation_pages=2189-2203; citation_doi=10.1016/j.mayocp.2020.07.024; citation_id=CR82"/> <meta name="citation_reference" content="citation_journal_title=Trends Endocrinol. Metab.; citation_title=ACE2, a new regulator of the renin-angiotensin system; citation_author=LM Burrell, CI Johnston, C Tikellis, ME Cooper; citation_volume=15; citation_publication_date=2004; citation_pages=166-169; citation_doi=10.1016/j.tem.2004.03.001; citation_id=CR83"/> <meta name="citation_reference" content="citation_journal_title=J. Biol. Chem.; citation_title=Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase; citation_author=C Vickers; citation_volume=277; citation_publication_date=2002; citation_pages=14838-14843; citation_doi=10.1074/jbc.M200581200; citation_id=CR84"/> <meta name="citation_reference" content="citation_journal_title=J. Med. Virol.; citation_title=Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19; citation_author=H Cheng, Y Wang, GQ Wang; citation_volume=92; citation_publication_date=2020; citation_pages=726-730; citation_doi=10.1002/jmv.25785; citation_id=CR85"/> <meta name="citation_reference" content="citation_journal_title=Gene; citation_title=SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype; citation_author=N Yamamoto; citation_volume=758; citation_publication_date=2020; citation_pages=144944; citation_doi=10.1016/j.gene.2020.144944; citation_id=CR86"/> <meta name="citation_reference" content="citation_journal_title=Heart Lung Circ.; citation_title=COVID-19-does this disease kill due to imbalance of the renin angiotensin system (RAS) caused by genetic and gender differences in the response to viral ACE2 attack?; citation_author=RH Arnold; citation_volume=29; citation_publication_date=2020; citation_pages=964-972; citation_doi=10.1016/j.hlc.2020.05.004; citation_id=CR87"/> <meta name="citation_reference" content="citation_journal_title=Immunity; citation_title=Cytokine storms: understanding COVID-19; citation_author=N Mangalmurti, CA Hunter; citation_volume=53; citation_publication_date=2020; citation_pages=19-25; citation_doi=10.1016/j.immuni.2020.06.017; citation_id=CR88"/> <meta name="citation_reference" content="citation_journal_title=Signal Transduct. Target. Ther.; citation_title=COVID-19: immunopathogenesis and immunotherapeutics; citation_author=L Yang; citation_volume=5; citation_publication_date=2020; citation_pages=128; citation_doi=10.1038/s41392-020-00243-2; citation_id=CR89"/> <meta name="citation_reference" content="citation_journal_title=Int. Immunopharmacol.; citation_title=The immune response and immune evasion characteristics in SARS-CoV, MERS-CoV, and SARS-CoV-2: vaccine design strategies; citation_author=S Molaei, M Dadkhah, V Asghariazar, C Karami, E Safarzadeh; citation_volume=92; citation_publication_date=2021; citation_pages=107051; citation_doi=10.1016/j.intimp.2020.107051; citation_id=CR90"/> <meta name="citation_reference" content="citation_journal_title=Int. Immunopharmacol.; citation_title=Immunology, immunopathogenesis and immunotherapeutics of COVID-19; an overview; citation_author=L Mohamed Khosroshahi, M Rokni, T Mokhtari, F Noorbakhsh; citation_volume=93; citation_publication_date=2021; citation_pages=107364; citation_doi=10.1016/j.intimp.2020.107364; citation_id=CR91"/> <meta name="citation_reference" content="citation_journal_title=Signal Transduct. Target. Ther.; citation_title=Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2; citation_author=M Catanzaro; citation_volume=5; citation_publication_date=2020; citation_pages=84; citation_doi=10.1038/s41392-020-0191-1; citation_id=CR92"/> <meta name="citation_reference" content="citation_journal_title=Int. Immunopharmacol.; citation_title=Recent findings on the coronavirus disease 2019 (COVID-19); immunopathogenesis and immunotherapeutics; citation_author=N Ebrahimi; citation_volume=89; citation_publication_date=2020; citation_pages=107082; citation_doi=10.1016/j.intimp.2020.107082; citation_id=CR93"/> <meta name="citation_reference" content="Kumar, S., Nyodu, R., Maurya, V. K. & Saxena, S. K. in Coronavirus Disease 2019 (COVID-19): Epidemiology, Pathogenesis, Diagnosis, and Therapeutics (ed. Saxena, S. K.) Ch. 5 (Springer Singapore, 2020)."/> <meta name="citation_reference" content="citation_journal_title=Am. J. Hum. Biol.; citation_title=Host genetic factors and susceptibility to SARS-CoV-2 infection; citation_author=TG Schurr; citation_volume=32; citation_publication_date=2020; citation_pages=e23497; citation_doi=10.1002/ajhb.23497; citation_id=CR95"/> <meta name="citation_reference" content="citation_journal_title=Allergy; citation_title=Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19; citation_author=AK Azkur; citation_volume=75; citation_publication_date=2020; citation_pages=1564-1581; citation_doi=10.1111/all.14364; citation_id=CR96"/> <meta name="citation_reference" content="citation_journal_title=Travel Med. Infect. Dis.; citation_title=An update on SARS-CoV-2/COVID-19 with particular reference to its clinical pathology, pathogenesis, immunopathology and mitigation strategies; citation_author=K Dhama; citation_volume=37; citation_publication_date=2020; citation_pages=101755; citation_doi=10.1016/j.tmaid.2020.101755; citation_id=CR97"/> <meta name="citation_reference" content="citation_journal_title=Int. J. Genomics; citation_title=Exploring host genetic polymorphisms involved in SARS-CoV infection outcomes: implications for personalized medicine in COVID-19; citation_author=O Ramos-Lopez; citation_volume=2020; citation_publication_date=2020; citation_pages=6901217; citation_doi=10.1155/2020/6901217; citation_id=CR98"/> <meta name="citation_reference" content="citation_journal_title=J. Infect. Dis.; citation_title=Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19; citation_author=F Syed; citation_volume=224; citation_publication_date=2021; citation_pages=60-69; citation_doi=10.1093/infdis/jiab167; citation_id=CR99"/> <meta name="citation_reference" content="citation_journal_title=Eur. J. Clin. Invest.; citation_title=Histopathology and genetic susceptibility in COVID-19 pneumonia; citation_author=J Thüsen, M Eerden; citation_volume=50; citation_publication_date=2020; citation_pages=e13259; citation_id=CR100"/> <meta name="citation_reference" content="citation_journal_title=Biol. Sex Differ.; citation_title=Impact of sex and gender on COVID-19 outcomes in Europe; citation_author=C Gebhard, V Regitz-Zagrosek, HK Neuhauser, R Morgan, SL Klein; citation_volume=11; citation_publication_date=2020; citation_pages=29; citation_doi=10.1186/s13293-020-00304-9; citation_id=CR101"/> <meta name="citation_reference" content="citation_journal_title=Immunogenetics; citation_title=The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection; citation_author=AK Maiti; citation_volume=72; citation_publication_date=2020; citation_pages=387-391; citation_doi=10.1007/s00251-020-01174-6; citation_id=CR102"/> <meta name="citation_reference" content="citation_journal_title=PLoS Genet.; citation_title=Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production; citation_author=JE Molineros; citation_volume=9; citation_publication_date=2013; citation_pages=e1003222; citation_doi=10.1371/journal.pgen.1003222; citation_id=CR103"/> <meta name="citation_reference" content="citation_journal_title=N. Engl. J. Med.; citation_title=Genomewide association study of severe COVID-19 with respiratory failure; citation_author=D Ellinghaus; citation_volume=383; citation_publication_date=2020; citation_pages=1522-1534; citation_doi=10.1056/NEJMoa2020283; citation_id=CR104"/> <meta name="citation_reference" content="Ellinghaus, D. et al. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. Preprint at https://www.medrxiv.org/content/early/2020/06/02/2020.05.31.20114991 (2020)."/> <meta name="citation_reference" content="citation_journal_title=Cell Discov.; citation_title=Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility; citation_author=F Wang; citation_volume=6; citation_publication_date=2020; citation_pages=83; citation_doi=10.1038/s41421-020-00231-4; citation_id=CR106"/> <meta name="citation_reference" content="citation_journal_title=Nature; citation_title=The major genetic risk factor for severe COVID-19 is inherited from Neanderthals; citation_author=H Zeberg, S Pääbo; citation_volume=587; citation_publication_date=2020; citation_pages=610-612; citation_doi=10.1038/s41586-020-2818-3; citation_id=CR107"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Med. Genet. A; citation_title=Risk variant for severe COVID-19 inherited from Neanderthals; citation_author=R Nelson; citation_volume=182; citation_publication_date=2020; citation_pages=2203-2204; citation_doi=10.1002/ajmg.a.61247; citation_id=CR108"/> <meta name="citation_reference" content="citation_journal_title=Nat. Rev. Genet.; citation_title=Host genetics and infectious disease: new tools, insights and translational opportunities; citation_author=AJ Kwok, A Mentzer, JC Knight; citation_volume=22; citation_publication_date=2021; citation_pages=137-153; citation_doi=10.1038/s41576-020-00297-6; citation_id=CR109"/> <meta name="citation_reference" content="citation_journal_title=BMJ; citation_title=Ethnicity and covid-19; citation_author=P Patel, L Hiam, A Sowemimo, D Devakumar, M McKee; citation_volume=369; citation_publication_date=2020; citation_pages=m2282; citation_doi=10.1136/bmj.m2282; citation_id=CR110"/> <meta name="citation_reference" content="citation_journal_title=Nonlinear Dyn.; citation_title=Interpreting, analysing and modelling COVID-19 mortality data; citation_author=D Sornette, E Mearns, M Schatz, K Wu, D Darcet; citation_volume=101; citation_publication_date=2020; citation_pages=1751-1776; citation_doi=10.1007/s11071-020-05966-z; citation_id=CR111"/> <meta name="citation_reference" content="citation_journal_title=Nature; citation_title=Factors associated with COVID-19-related death using OpenSAFELY; citation_author=EJ Williamson; citation_volume=584; citation_publication_date=2020; citation_pages=430-436; citation_doi=10.1038/s41586-020-2521-4; citation_id=CR112"/> <meta name="citation_reference" content="citation_journal_title=PLoS Med.; citation_title=Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: a nationwide cohort study; citation_author=CT Rentsch; citation_volume=17; citation_publication_date=2020; citation_pages=e1003379; citation_doi=10.1371/journal.pmed.1003379; citation_id=CR113"/> <meta name="citation_reference" content="citation_journal_title=JAMA; citation_title=COVID-19 and racial/ethnic disparities; citation_author=M Webb Hooper, AM Nápoles, EJ Pérez-Stable; citation_volume=323; citation_publication_date=2020; citation_pages=2466-2467; citation_doi=10.1001/jama.2020.8598; citation_id=CR114"/> <meta name="citation_reference" content="citation_journal_title=Med. Intens.; citation_title=HLA genetic polymorphisms and prognosis of patients with COVID-19; citation_author=L Lorente; citation_volume=45; citation_publication_date=2021; citation_pages=96-103; citation_doi=10.1016/j.medin.2020.08.004; citation_id=CR115"/> <meta name="citation_reference" content="citation_journal_title=Cell Syst.; citation_title=Estimating the binding of SARS-CoV-2 peptides to HLA class I in human subpopulations using artificial neural networks; citation_author=CAM La Porta, S Zapperi; citation_volume=11; citation_publication_date=2020; citation_pages=412-417; citation_doi=10.1016/j.cels.2020.08.011; citation_id=CR116"/> <meta name="citation_reference" content="citation_journal_title=Immun. Inflamm. Dis.; citation_title=Association between HLA gene polymorphisms and mortality of COVID-19: an in silico analysis; citation_author=Y Tomita, T Ikeda, R Sato, T Sakagami; citation_volume=8; citation_publication_date=2020; citation_pages=684-694; citation_doi=10.1002/iid3.358; citation_id=CR117"/> <meta name="citation_reference" content="citation_journal_title=HLA; citation_title=Association of HLA-B22 serotype with SARS-CoV-2 susceptibility in Hong Kong Chinese patients; citation_author=YL Yung; citation_volume=97; citation_publication_date=2021; citation_pages=127-132; citation_doi=10.1111/tan.14135; citation_id=CR118"/> <meta name="citation_reference" content="citation_journal_title=HLA; citation_title=Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide; citation_author=R Barquera; citation_volume=96; citation_publication_date=2020; citation_pages=277-298; citation_doi=10.1111/tan.13956; citation_id=CR119"/> <meta name="citation_reference" content="citation_journal_title=J. Cell. Physiol.; citation_title=An updated review of the association of host genetic factors with susceptibility and resistance to COVID-19; citation_author=S Mohammadpour, A Torshizi Esfahani, M Halaji, M Lak, R Ranjbar; citation_volume=236; citation_publication_date=2021; citation_pages=49-54; citation_id=CR120"/> <meta name="citation_reference" content="citation_journal_title=FASEB J.; citation_title=Genetic gateways to COVID-19 infection: implications for risk, severity, and outcomes; citation_author=M Debnath, M Banerjee, M Berk; citation_volume=34; citation_publication_date=2020; citation_pages=8787-8795; citation_doi=10.1096/fj.202001115R; citation_id=CR121"/> <meta name="citation_reference" content="citation_journal_title=J. Hum. Genet.; citation_title=Bioinformatic prediction of potential T cell epitopes for SARS-CoV-2; citation_author=K Kiyotani, Y Toyoshima, K Nemoto, Y Nakamura; citation_volume=65; citation_publication_date=2020; citation_pages=569-575; citation_doi=10.1038/s10038-020-0771-5; citation_id=CR122"/> <meta name="citation_reference" content="citation_journal_title=Front. Immunol.; citation_title=Human leukocyte antigen complex and other immunogenetic and clinical factors influence susceptibility or protection to SARS-CoV-2 infection and severity of the disease course. The Sardinian experience; citation_author=R Littera; citation_volume=11; citation_publication_date=2020; citation_pages=605688; citation_doi=10.3389/fimmu.2020.605688; citation_id=CR123"/> <meta name="citation_reference" content="citation_journal_title=PLoS One; citation_title=Clinical, regional, and genetic characteristics of Covid-19 patients from UK Biobank; citation_author=DA Kolin, S Kulm, PJ Christos, O Elemento; citation_volume=15; citation_publication_date=2020; citation_pages=e0241264; citation_doi=10.1371/journal.pone.0241264; citation_id=CR124"/> <meta name="citation_reference" content="citation_journal_title=HLA; citation_title=Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19); citation_author=W Wang, W Zhang, J Zhang, J He, F Zhu; citation_volume=96; citation_publication_date=2020; citation_pages=194-196; citation_doi=10.1111/tan.13941; citation_id=CR125"/> <meta name="citation_reference" content="citation_journal_title=HLA; citation_title=HLA allele frequencies and susceptibility to COVID-19 in a group of 99 Italian patients; citation_author=A Novelli; citation_volume=96; citation_publication_date=2020; citation_pages=610-614; citation_doi=10.1111/tan.14047; citation_id=CR126"/> <meta name="citation_reference" content="citation_journal_title=Int. J. Mol. Sci.; citation_title=HLA-B*44 and C*01 prevalence correlates with COVID-19 spreading across Italy; citation_author=P Correale; citation_volume=21; citation_publication_date=2020; citation_pages=5205; citation_doi=10.3390/ijms21155205; citation_id=CR127"/> <meta name="citation_reference" content="citation_journal_title=F1000Res.; citation_title=Most Japanese individuals are genetically predisposed to recognize an immunogenic protein fragment shared between COVID-19 and common cold coronaviruses; citation_author=J Dijkstra, A Frenette, B Dixon; citation_volume=10; citation_publication_date=2021; citation_pages=196; citation_doi=10.12688/f1000research.51479.1; citation_id=CR128"/> <meta name="citation_reference" content="citation_journal_title=Clin. Immunol.; citation_title=Possible role of HLA class-I genotype in SARS-CoV-2 infection and progression: a pilot study in a cohort of Covid-19 Spanish patients; citation_author=I Iturrieta-Zuazo; citation_volume=219; citation_publication_date=2020; citation_pages=108572; citation_doi=10.1016/j.clim.2020.108572; citation_id=CR129"/> <meta name="citation_reference" content="citation_journal_title=J. Transl. Med.; citation_title=Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of COVID-19; citation_author=S Pisanti; citation_volume=18; citation_publication_date=2020; citation_doi=10.1186/s12967-020-02515-5; citation_id=CR130"/> <meta name="citation_reference" content="citation_journal_title=Sci. Rep.; citation_title=Identification and validation of 174 COVID-19 vaccine candidate epitopes reveals low performance of common epitope prediction tools; citation_author=M Prachar; citation_volume=10; citation_publication_date=2020; citation_doi=10.1038/s41598-020-77466-4; citation_id=CR131"/> <meta name="citation_reference" content="citation_journal_title=Blood Rev.; citation_title=The impact of ABO blood group on COVID-19 infection risk and mortality: a systematic review and meta-analysis; citation_author=N Liu; citation_volume=48; citation_publication_date=2020; citation_pages=100785; citation_doi=10.1016/j.blre.2020.100785; citation_id=CR132"/> <meta name="citation_reference" content="citation_journal_title=Front. Cell. Infect. Microbiol.; citation_title=Association between ABO blood group system and COVID-19 susceptibility in Wuhan; citation_author=Q Fan; citation_volume=10; citation_publication_date=2020; citation_pages=404; citation_doi=10.3389/fcimb.2020.00404; citation_id=CR133"/> <meta name="citation_reference" content="citation_journal_title=Transfusion; citation_title=Association of ABO blood group and secretor phenotype with severe COVID-19; citation_author=L Valenti; citation_volume=60; citation_publication_date=2020; citation_pages=3067-3070; citation_doi=10.1111/trf.16130; citation_id=CR134"/> <meta name="citation_reference" content="citation_journal_title=Eur. J. Prev. Cardiol.; citation_title=ABO blood group predisposes to COVID-19 severity and cardiovascular diseases; citation_author=X Dai; citation_volume=27; citation_publication_date=2020; citation_pages=1436-1437; citation_doi=10.1177/2047487320922370; citation_id=CR135"/> <meta name="citation_reference" content="citation_journal_title=Clin. Chem. Lab. Med.; citation_title=ABO blood group and von Willebrand factor: biological implications; citation_author=M Franchini, S Crestani, F Frattini, C Sissa, C Bonfanti; citation_volume=52; citation_publication_date=2014; citation_pages=1273-1276; citation_doi=10.1515/cclm-2014-0564; citation_id=CR136"/> <meta name="citation_reference" content="citation_journal_title=Ann. Hum. Genet.; citation_title=Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus; citation_author=C Terao; citation_volume=77; citation_publication_date=2013; citation_pages=465-471; citation_doi=10.1111/ahg.12034; citation_id=CR137"/> <meta name="citation_reference" content="citation_journal_title=Pharmacogenomics J.; citation_title=A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor; citation_author=CM Chung; citation_volume=10; citation_publication_date=2010; citation_pages=537-544; citation_doi=10.1038/tpj.2009.70; citation_id=CR138"/> <meta name="citation_reference" content="Yamagata University Genomic Cohort Consortium (YUGCC) Pleiotropic effect of common variants at ABO Glycosyltranferase locus in 9q32 on plasma levels of pancreatic lipase and angiotensin converting enzyme. PLoS One 9, e55903 (2014)."/> <meta name="citation_reference" content="citation_journal_title=Cell Cycle; citation_title=Dipeptidyl peptidase 2 is an essential survival factor in the regulation of cell quiescence; citation_author=DA Mele, P Bista, DV Baez, BT Huber; citation_volume=8; citation_publication_date=2009; citation_pages=2425-2434; citation_doi=10.4161/cc.8.15.9144; citation_id=CR140"/> <meta name="citation_reference" content="citation_journal_title=J. Infect. Dis.; citation_title=Minor allele of interferon-induced transmembrane protein 3 polymorphism (rs12252) is covered against severe acute respiratory syndrome coronavirus 2 infection and mortality: a worldwide epidemiological investigation; citation_author=A Pati, S Padhi, S Suvankar, AK Panda; citation_volume=223; citation_publication_date=2021; citation_pages=175-178; citation_doi=10.1093/infdis/jiaa630; citation_id=CR141"/> <meta name="citation_reference" content="citation_journal_title=J. Infect. Dis.; citation_title=Interferon-induced transmembrane protein 3 genetic variant rs12252-C associated with disease severity in coronavirus disease 2019; citation_author=Y Zhang; citation_volume=222; citation_publication_date=2020; citation_pages=34-37; citation_doi=10.1093/infdis/jiaa224; citation_id=CR142"/> <meta name="citation_reference" content="citation_journal_title=Nat. Med.; citation_title=Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19; citation_author=I Thevarajan; citation_volume=26; citation_publication_date=2020; citation_pages=453-455; citation_doi=10.1038/s41591-020-0819-2; citation_id=CR143"/> <meta name="citation_reference" content="citation_journal_title=Cytokine; citation_title=The interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19; citation_author=J Gómez; citation_volume=137; citation_publication_date=2021; citation_pages=155354; citation_doi=10.1016/j.cyto.2020.155354; citation_id=CR144"/> <meta name="citation_reference" content="citation_journal_title=PeerJ; citation_title=The frequency of combined IFITM3 haplotype involving the reference alleles of both rs12252 and rs34481144 is in line with COVID-19 standardized mortality ratio of ethnic groups in England; citation_author=D Nikoloudis, D Kountouras, A Hiona; citation_volume=8; citation_publication_date=2020; citation_pages=e10402; citation_doi=10.7717/peerj.10402; citation_id=CR145"/> <meta name="citation_reference" content="citation_journal_title=Nat. Med.; citation_title=SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans; citation_author=EK Allen; citation_volume=23; citation_publication_date=2017; citation_pages=975-983; citation_doi=10.1038/nm.4370; citation_id=CR146"/> <meta name="citation_reference" content="citation_journal_title=Andrology; citation_title=New point mutation in Golga3 causes multiple defects in spermatogenesis; citation_author=LF Bentson; citation_volume=1; citation_publication_date=2013; citation_pages=440-450; citation_doi=10.1111/j.2047-2927.2013.00070.x; citation_id=CR147"/> <meta name="citation_reference" content="citation_journal_title=Nature; citation_title=A SARS-CoV-2 protein interaction map reveals targets for drug repurposing; citation_author=DE Gordon; citation_volume=583; citation_publication_date=2020; citation_pages=459-468; citation_doi=10.1038/s41586-020-2286-9; citation_id=CR148"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection; citation_author=J Wei; citation_volume=184; citation_publication_date=2021; citation_pages=76-91.e13; citation_doi=10.1016/j.cell.2020.10.028; citation_id=CR149"/> <meta name="citation_reference" content="citation_journal_title=Heliyon; citation_title=HMGB1 as a potential biomarker and therapeutic target for severe COVID-19; citation_author=R Chen; citation_volume=6; citation_publication_date=2020; citation_pages=e05672; citation_doi=10.1016/j.heliyon.2020.e05672; citation_id=CR150"/> <meta name="citation_reference" content="citation_journal_title=Heliyon; citation_title=ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: a time to implement precision medicine against COVID-19; citation_author=F Al-Mulla; citation_volume=7; citation_publication_date=2021; citation_pages=e06133; citation_doi=10.1016/j.heliyon.2021.e06133; citation_id=CR151"/> <meta name="citation_reference" content="citation_journal_title=Genes; citation_title=Genetic hypothesis and pharmacogenetics side of renin-angiotensin-system in COVID-19; citation_author=D Gemmati, V Tisato; citation_volume=11; citation_publication_date=2020; citation_pages=1044; citation_doi=10.3390/genes11091044; citation_id=CR152"/> <meta name="citation_reference" content="citation_journal_title=IJCB; citation_title=Alteration of splicing pattern on angiotensin-converting enzyme gene due to the insertion of Alu elements; citation_author=DL Purwaningroom, M Saifurrohman, null Widodo, JF Putri, M Lukitasari; citation_volume=4; citation_publication_date=2015; citation_pages=53-58; citation_id=CR153"/> <meta name="citation_reference" content="citation_journal_title=Int. J. Mol. Sci.; citation_title=COVID-19 and individual genetic susceptibility/receptivity: role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-chromosome in males?; citation_author=D Gemmati; citation_volume=21; citation_publication_date=2020; citation_pages=3474; citation_doi=10.3390/ijms21103474; citation_id=CR154"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Pathol.; citation_title=Angiotensin-converting enzyme gene polymorphism and severe lung injury in patients with coronavirus disease 2019; citation_author=H Zheng, JJ Cao; citation_volume=190; citation_publication_date=2020; citation_pages=2013-2017; citation_doi=10.1016/j.ajpath.2020.07.009; citation_id=CR155"/> <meta name="citation_reference" content="Delanghe, J. R., Speeckaert, M. M. & De Buyzere, M. L. COVID-19 infections are also affected by human ACE1 D/I polymorphism. Clin. Chem. Lab. Med. 58, 1125–1126 (2020)."/> <meta name="citation_reference" content="citation_journal_title=Clin. Chim. Acta; citation_title=The host’s angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections; citation_author=JR Delanghe, MM Speeckaert, ML Buyzere; citation_volume=505; citation_publication_date=2020; citation_pages=192-193; citation_doi=10.1016/j.cca.2020.03.031; citation_id=CR157"/> <meta name="citation_reference" content="citation_journal_title=Endocrine; citation_title=Worldwide ACE (I/D) polymorphism may affect COVID-19 recovery rate: an ecological meta-regression; citation_author=N Hatami; citation_volume=68; citation_publication_date=2020; citation_pages=479-484; citation_doi=10.1007/s12020-020-02381-7; citation_id=CR158"/> <meta name="citation_reference" content="citation_journal_title=Eur. J. Hum. Genet.; citation_title=Worldwide spatial genetic structure of angiotensin-converting enzyme gene: a new evolutionary ecological evidence for the thrifty genotype hypothesis; citation_author=X Li, X Sun, L Jin, F Xue; citation_volume=19; citation_publication_date=2011; citation_pages=1002-1008; citation_doi=10.1038/ejhg.2011.66; citation_id=CR159"/> <meta name="citation_reference" content="citation_journal_title=Hum. Genomics; citation_title=Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity; citation_author=C Anastassopoulou, Z Gkizarioti, GP Patrinos, A Tsakris; citation_volume=14; citation_publication_date=2020; citation_doi=10.1186/s40246-020-00290-4; citation_id=CR160"/> <meta name="citation_reference" content="citation_journal_title=Front. Immunol.; citation_title=Commentary: APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort; citation_author=K Kasparian, D Graykowski, E Cudaback; citation_volume=11; citation_publication_date=2020; citation_pages=1939; citation_doi=10.3389/fimmu.2020.01939; citation_id=CR161"/> <meta name="citation_reference" content="citation_journal_title=Curr. Atheroscler. Rep.; citation_title=Biological factors linking APOE ε4 variant and severe COVID-19; citation_author=J Inal; citation_volume=22; citation_publication_date=2020; citation_pages=70; citation_doi=10.1007/s11883-020-00896-y; citation_id=CR162"/> <meta name="citation_reference" content="citation_journal_title=J. Gerontol. A Biol. Sci. Med. Sci.; citation_title=APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort; citation_author=CL Kuo; citation_volume=75; citation_publication_date=2020; citation_pages=2231-2232; citation_doi=10.1093/gerona/glaa131; citation_id=CR163"/> <meta name="citation_reference" content="citation_journal_title=Curr. Res. Transl. Med.; citation_title=Sex-mediated effects of ACE2 and TMPRSS2 on the incidence and severity of COVID-19; the need for genetic implementation; citation_author=M Alshahawey, M Raslan, N Sabri; citation_volume=68; citation_publication_date=2020; citation_pages=149-150; citation_doi=10.1016/j.retram.2020.08.002; citation_id=CR164"/> <meta name="citation_reference" content="citation_journal_title=Front. Med.; citation_title=The pursuit of COVID-19 biomarkers: putting the spotlight on ACE2 and TMPRSS2 regulatory sequences; citation_author=A Barash, Y Machluf, I Ariel, Y Dekel; citation_volume=7; citation_publication_date=2020; citation_pages=582793; citation_doi=10.3389/fmed.2020.582793; citation_id=CR165"/> <meta name="citation_reference" content="citation_journal_title=Microb. Pathogenesis; citation_title=ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease; citation_author=H Singh, R Choudhari, V Nema, AA Khan; citation_volume=150; citation_publication_date=2021; citation_pages=104621; citation_doi=10.1016/j.micpath.2020.104621; citation_id=CR166"/> <meta name="citation_reference" content="citation_journal_title=Cell Biol. Int.; citation_title=Genetic and epigenetic factors associated with increased severity of Covid-19; citation_author=Z Yildirim, OS Sahin, S Yazar, V Bozok Cetintas; citation_volume=45; citation_publication_date=2021; citation_pages=1158-1174; citation_doi=10.1002/cbin.11572; citation_id=CR167"/> <meta name="citation_reference" content="citation_journal_title=Ann. Lab. Med.; citation_title=Role of genetic variants and gene expression in the susceptibility and severity of COVID-19; citation_author=S Choudhary, K Sreenivasulu, P Mitra, S Misra, P Sharma; citation_volume=41; citation_publication_date=2021; citation_pages=129-138; citation_doi=10.3343/alm.2021.41.2.129; citation_id=CR168"/> <meta name="citation_reference" content="citation_journal_title=Biochem. Biophys. Res. Commun.; citation_title=Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents; citation_author=LM Irham; citation_volume=529; citation_publication_date=2020; citation_pages=263-269; citation_doi=10.1016/j.bbrc.2020.05.179; citation_id=CR169"/> <meta name="citation_reference" content="citation_journal_title=Eur. J. Clin. Microbiol. Infect. Dis.; citation_title=Expression and co-expression analyses of TMPRSS2, a key element in COVID-19; citation_author=F Piva, B Sabanovic, M Cecati, M Giulietti; citation_volume=40; citation_publication_date=2021; citation_pages=451-455; citation_doi=10.1007/s10096-020-04089-y; citation_id=CR170"/> <meta name="citation_reference" content="citation_journal_title=BMC Med.; citation_title=New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis; citation_author=Y Hou; citation_volume=18; citation_publication_date=2020; citation_doi=10.1186/s12916-020-01673-z; citation_id=CR171"/> <meta name="citation_reference" content="citation_journal_title=J. Endocrinol. Invest.; citation_title=& Di Nisio, A. Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome; citation_author=C Foresta, MS Rocca; citation_volume=16; citation_publication_date=2020; citation_pages=1-6; citation_id=CR172"/> <meta name="citation_reference" content="citation_journal_title=Int. Arch. Allergy Immunol.; citation_title=The role of genetic sex and mitochondria in response to COVID-19 infection; citation_author=M Kloc, RM Ghobrial, JZ Kubiak; citation_volume=181; citation_publication_date=2020; citation_pages=629-634; citation_doi=10.1159/000508560; citation_id=CR173"/> <meta name="citation_reference" content="citation_journal_title=Crit. Care; citation_title=Molecular mechanisms of sex bias differences in COVID-19 mortality; citation_author=Y Li, M Jerkic, AS Slutsky, H Zhang; citation_volume=24; citation_publication_date=2020; citation_doi=10.1186/s13054-020-03118-8; citation_id=CR174"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Physiol. Heart Circ. Physiol.; citation_title=Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones; citation_author=A Viveiros; citation_volume=320; citation_publication_date=2021; citation_pages=H296-H304; citation_doi=10.1152/ajpheart.00755.2020; citation_id=CR175"/> <meta name="citation_reference" content="citation_journal_title=Front. Immunol.; citation_title=What’s sex got to do with COVID-19? Gender-based differences in the host immune response to coronaviruses; citation_author=N Gadi, SC Wu, AP Spihlman, VR Moulton; citation_volume=11; citation_publication_date=2020; citation_pages=2147; citation_doi=10.3389/fimmu.2020.02147; citation_id=CR176"/> <meta name="citation_reference" content="citation_journal_title=Proc. Natl. Acad. Sci. USA; citation_title=Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X; citation_author=J Wang; citation_volume=113; citation_publication_date=2016; citation_pages=E2029-E2038; citation_id=CR177"/> <meta name="citation_reference" content="citation_journal_title=Cureus; citation_title=The role of sex in the risk of mortality from COVID-19 amongst adult patients: a systematic review; citation_author=M Kelada, A Anto, K Dave, SN Saleh; citation_volume=12; citation_publication_date=2020; citation_pages=e10114; citation_id=CR178"/> <meta name="citation_reference" content="citation_journal_title=Br. J. 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data-test="article-title" data-article-title="">Human genetic basis of coronavirus disease 2019</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Hao-Deng-Aff1-Aff2-Aff3-Aff4" data-author-popup="auth-Hao-Deng-Aff1-Aff2-Aff3-Aff4" data-author-search="Deng, Hao" data-corresp-id="c1">Hao Deng<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0003-3240-4352"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0003-3240-4352</a></span><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Xue-Yan-Aff1-Aff2-Aff3" data-author-popup="auth-Xue-Yan-Aff1-Aff2-Aff3" data-author-search="Yan, Xue">Xue Yan</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a></sup><sup class="u-js-hide"> <a href="#na1">na1</a></sup> & </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Lamei-Yuan-Aff1-Aff2-Aff3-Aff4" data-author-popup="auth-Lamei-Yuan-Aff1-Aff2-Aff3-Aff4" data-author-search="Yuan, Lamei">Lamei Yuan</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a></sup> </li></ul> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/sigtrans" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Signal Transduction and Targeted Therapy</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 6</b>, Article number: <span data-test="article-number">344</span> (<span data-test="article-publication-year">2021</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">15k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p 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href="/subjects/medical-genetics" data-track="click" data-track-action="view subject" data-track-label="link">Medical genetics</a></li><li class="c-article-subject-list__subject"><a href="/subjects/predictive-markers" data-track="click" data-track-action="view subject" data-track-label="link">Predictive markers</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in considerable morbidity and mortality worldwide. COVID-19 incidence, severity, and mortality rates differ greatly between populations, genders, ABO blood groups, human leukocyte antigen (HLA) genotypes, ethnic groups, and geographic backgrounds. This highly heterogeneous SARS-CoV-2 infection is multifactorial. Host genetic factors such as variants in the angiotensin-converting enzyme gene (<i>ACE</i>), the angiotensin-converting enzyme 2 gene (<i>ACE2</i>), the transmembrane protease serine 2 gene (<i>TMPRSS2</i>), along with HLA genotype, and ABO blood group help to explain individual susceptibility, severity, and outcomes of COVID-19. This review is focused on COVID-19 clinical and viral characteristics, pathogenesis, and genetic findings, with particular attention on genetic diversity and variants. The human genetic basis could provide scientific bases for disease prediction and targeted therapy to address the COVID-19 scourge.</p></div></div></section> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41431-022-01121-x/MediaObjects/41431_2022_1121_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41431-022-01121-x?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41431-022-01121-x">Host genetic basis of COVID-19: from methodologies to genes </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">27 May 2022</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41588-021-01006-7/MediaObjects/41588_2021_1006_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41588-021-01006-7?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1038/s41588-021-01006-7">Genome-wide analysis provides genetic evidence that ACE2 influences COVID-19 risk and yields risk scores associated with severe disease </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">03 March 2022</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41576-022-00478-5/MediaObjects/41576_2022_478_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41576-022-00478-5?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41576-022-00478-5">The human genetic epidemiology of COVID-19 </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">02 May 2022</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1740503947, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"><p>Coronavirus disease 2019 (COVID-19) is this century’s third plague and was declared as the sixth international concerned public health emergency by the World Health Organization (WHO) on 30 January 2020.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Yoo, J. H. The fight against the 2019-nCoV outbreak: an arduous march has just begun. J. Korean Med. Sci. 35, e56 (2020)." href="/articles/s41392-021-00736-8#ref-CR1" id="ref-link-section-d5157390e445">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Lai, C. C., Shih, T. P., Ko, W. C., Tang, H. J. & Hsueh, P. R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int. J. Antimicrob. Agents 55, 105924 (2020)." href="/articles/s41392-021-00736-8#ref-CR2" id="ref-link-section-d5157390e448">2</a></sup> The responsible pathogen is a previously unknown RNA coronavirus.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Yoo, J. H. The fight against the 2019-nCoV outbreak: an arduous march has just begun. J. Korean Med. Sci. 35, e56 (2020)." href="/articles/s41392-021-00736-8#ref-CR1" id="ref-link-section-d5157390e452">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020)." href="/articles/s41392-021-00736-8#ref-CR3" id="ref-link-section-d5157390e455">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Ravaioli, S. et al. ACE2 and TMPRSS2 potential involvement in genetic susceptibility to SARS-CoV-2 in cancer patients. Cell Transplant. 29, 963689720968749 (2020)." href="/articles/s41392-021-00736-8#ref-CR4" id="ref-link-section-d5157390e458">4</a></sup> It was designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Gorbalenya, A. E. et al. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat. Microbiol. 5, 536–544 (2020)." href="/articles/s41392-021-00736-8#ref-CR5" id="ref-link-section-d5157390e462">5</a></sup> As of 17 May 2021, the COVID-19 pandemic has resulted in 162,494,817 cases and 3,494,424 deaths worldwide (<a href="https://covid19.who.int/">https://covid19.who.int/</a>). COVID-19 is highly heterogeneous and its severity may relate to multiple factors including health care, quarantine effectiveness, governmental policies, societal norms of behavior, economics, cultural practices, climate, pollution, and viral characteristics, as well as host-associated factors.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Hu, J., Li, C., Wang, S., Li, T. & Zhang, H. Genetic variants are identified to increase risk of COVID-19 related mortality from UK biobank data. Hum. Genomics 15, 10 (2021)." href="#ref-CR6" id="ref-link-section-d5157390e473">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Zbinden-Foncea, H., Francaux, M., Deldicque, L. & Hawley, J. A. Does high cardiorespiratory fitness confer some protection against proinflammatory responses after infection by SARS-CoV-2? Obesity 28, 1378–1381 (2020)." href="#ref-CR7" id="ref-link-section-d5157390e473_1">7</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Calcagnile, M. et al. Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 spike protein. Biochimie 180, 143–148 (2021)." href="#ref-CR8" id="ref-link-section-d5157390e473_2">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Sakuraba, A., Haider, H. & Sato, T. Population difference in allele frequency of HLA-C*05 and its correlation with COVID-19 mortality. Viruses 12, 1333 (2020)." href="#ref-CR9" id="ref-link-section-d5157390e473_3">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Ikitimur, H. et al. Determining host factors contributing to disease severity in a family cluster of 29 hospitalized SARS-CoV-2 patients: could genetic factors be relevant in the clinical course of COVID-19? J. Med. Virol. 93, 357–365 (2021)." href="/articles/s41392-021-00736-8#ref-CR10" id="ref-link-section-d5157390e476">10</a></sup> In the aspect of host-associated factors, in addition to age (>60 years), initial health status, pre-existing diseases, smoking history, and previous vaccinations, individual genetic basis contributes to individual susceptibility, severity, and outcomes of COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Zbinden-Foncea, H., Francaux, M., Deldicque, L. & Hawley, J. A. Does high cardiorespiratory fitness confer some protection against proinflammatory responses after infection by SARS-CoV-2? Obesity 28, 1378–1381 (2020)." href="/articles/s41392-021-00736-8#ref-CR7" id="ref-link-section-d5157390e481">7</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Rajarshi, K. et al. Essential functional molecules associated with SARS-CoV-2 infection: potential therapeutic targets for COVID-19. Gene 768, 145313 (2021)." href="/articles/s41392-021-00736-8#ref-CR11" id="ref-link-section-d5157390e484">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Ovsyannikova, I. G., Haralambieva, I. H., Crooke, S. N., Poland, G. A. & Kennedy, R. B. The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity. Immunol. Rev. 296, 205–219 (2020)." href="/articles/s41392-021-00736-8#ref-CR12" id="ref-link-section-d5157390e487">12</a></sup> Classical twin studies indicated 31% heritability for predicted COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Williams, F. M. K. et al. Self-reported symptoms of COVID-19, including symptoms most predictive of SARS-CoV-2 infection, are heritable. Twin Res. Hum. Genet. 23, 316–321 (2020)." href="/articles/s41392-021-00736-8#ref-CR13" id="ref-link-section-d5157390e491">13</a></sup> Human genetic basis may implicate in significant diversities of COVID-19 among populations with different genders, ABO blood groups, human leukocyte antigen (HLA) genotypes, ethnic groups, and geographic backgrounds.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Hu, J., Li, C., Wang, S., Li, T. & Zhang, H. Genetic variants are identified to increase risk of COVID-19 related mortality from UK biobank data. Hum. Genomics 15, 10 (2021)." href="/articles/s41392-021-00736-8#ref-CR6" id="ref-link-section-d5157390e495">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Agrawal, H. et al. An assessment on impact of COVID-19 infection in a gender specific manner. Stem Cell Rev. Rep. 17, 94–112 (2021)." href="#ref-CR14" id="ref-link-section-d5157390e498">14</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Zhao, J. et al. Relationship between the ABO blood group and the coronavirus disease 2019 (COVID-19) susceptibility. Clin. Infect. Dis. 73, 328–331 (2021)." href="#ref-CR15" id="ref-link-section-d5157390e498_1">15</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Nguyen, A. et al. Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2. J. Virol. 94 e00510–20 (2020)." href="/articles/s41392-021-00736-8#ref-CR16" id="ref-link-section-d5157390e501">16</a></sup> Several gene variants related to gene expression and protein function changes were reported as explaining the individual susceptibility, severity, and outcomes.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Ovsyannikova, I. G., Haralambieva, I. H., Crooke, S. N., Poland, G. A. & Kennedy, R. B. The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity. Immunol. Rev. 296, 205–219 (2020)." href="/articles/s41392-021-00736-8#ref-CR12" id="ref-link-section-d5157390e505">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Gómez, J. et al. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene 762, 145102 (2020)." href="/articles/s41392-021-00736-8#ref-CR17" id="ref-link-section-d5157390e508">17</a></sup></p><p>In this review, clinical and viral characteristics, pathogenesis, and the human genetic basis associated with COVID-19 are investigated. Focus is on the protective and risk effects of variants in related genes such as the angiotensin-converting enzyme gene (<i>ACE</i>), the angiotensin-converting enzyme 2 gene (<i>ACE2</i>), the transmembrane protease serine 2 gene (<i>TMPRSS2</i>), and ABO blood groups and HLA genotypes (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41392-021-00736-8#Tab1">1</a> and Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41392-021-00736-8#Fig1">1</a>).</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Summary of human genes associated with COVID-19</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/s41392-021-00736-8/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Fig. 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41392-021-00736-8/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-021-00736-8/MediaObjects/41392_2021_736_Fig1_HTML.png?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-021-00736-8/MediaObjects/41392_2021_736_Fig1_HTML.png" alt="figure 1" loading="lazy" width="685" height="460"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>Pathogenesis of SARS-CoV-2 and genetic variants associated with COVID-19. After the recognition of ACE2, DPP4, GRP78, and AXL receptors and the priming by TMPRSS2, FURIN, and NRP1, as well as cathepsin B/L, SARS-CoV-2 enters cells and starts the replication process to assemble and release. Activated AR induces <i>TMPRSS2</i> expression. ACE/Ang II/AT1R and ACE2/Ang-(1–7)/MasR axes regulate RAAS to involve in COVID-19. The risk (black), protective (green), and uncertain (blue) variants or alleles or haplotypes for COVID-19 are highlighted. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, ACE2 angiotensin-converting enzyme 2, DPP4 dipeptidyl peptidase 4, GRP78 glucose-regulated protein-78, AXL anexelekto, TMPRSS2 transmembrane protease serine 2, FURIN furin, paired basic amino acid-cleaving enzyme, NRP1 neuropilin-1, AR androgen receptor, AGT angiotensinogen, Ang angiotensin, ACE angiotensin-converting enzyme, AT1R angiotensin II type 1 receptor, MasR Mas receptor, <i>TLR7</i> the Toll-like receptor 7 gene, <i>IFITM3</i> the interferon induced transmembrane protein 3 gene, HLA human leukocyte antigen, <i>GOLGA3</i> the golgin A3 gene, <i>ABO</i> the ABO, alpha 1–3-<i>N</i>-acetylgalactosaminyltransferase and alpha 1–3-galactosyltransferase gene, <i>APOE</i> the apolipoprotein E gene, <i>IFIH1</i> the interferon induced with helicase C domain 1 gene, MAVS mitochondrial antiviral signaling protein, ER endoplasmic reticulum</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41392-021-00736-8/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></section><section data-title="Clinical characteristics"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Clinical characteristics</h2><div class="c-article-section__content" id="Sec2-content"><p>The COVID-19 clinical spectrum is heterogeneous (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41392-021-00736-8#Fig2">2</a>) and ranges from asymptomatic (<span class="stix">∼</span>5.4–15.0%), mild–moderate (<span class="stix">∼</span>50.0%), severe (<span class="stix">∼</span>13.8–16.0%) to critical (<span class="stix">∼</span>4.0–25.6%) status.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Rahimi, A., Mirzazadeh, A. & Tavakolpour, S. Genetics and genomics of SARS-CoV-2: a review of the literature with the special focus on genetic diversity and SARS-CoV-2 genome detection. Genomics 113, 1221–1232 (2021)." href="#ref-CR18" id="ref-link-section-d5157390e2823">18</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Nascimento, V. A. D. et al. Genomic and phylogenetic characterisation of an imported case of SARS-CoV-2 in Amazonas State, Brazil. Mem. Inst. Oswaldo Cruz 115, e200310 (2020)." href="#ref-CR19" id="ref-link-section-d5157390e2823_1">19</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dobrindt, K. et al. Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection. Stem Cell Rep. 16, 505–518 (2021)." href="#ref-CR20" id="ref-link-section-d5157390e2823_2">20</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Jutzeler, C. R. et al. Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: a systematic review and meta-analysis. Travel Med. Infect. Dis. 37, 101825 (2020)." href="#ref-CR21" id="ref-link-section-d5157390e2823_3">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Pormohammad, A. et al. Clinical characteristics, laboratory findings, radiographic signs and outcomes of 61,742 patients with confirmed COVID-19 infection: a systematic review and meta-analysis. Microb. Pathog. 147, 104390 (2020)." href="/articles/s41392-021-00736-8#ref-CR22" id="ref-link-section-d5157390e2826">22</a></sup> Typical symptoms in most patients are mild and nonspecific, including fever (<span class="stix">∼</span>72.4–91.3%), cough (<span class="stix">∼</span>53.8–68.6%), smell dysfunction (<span class="stix">∼</span>59.9%), taste dysfunction (<span class="stix">∼</span>57.5%), fatigue (<span class="stix">∼</span>25.0–51.0%), dyspnea (<span class="stix">∼</span>12.3–30.4%), myalgia (<span class="stix">∼</span>15.3–28.5%), expectoration (<span class="stix">∼</span>23.0–28.2%), chest discomfort (<span class="stix">∼</span>14.9–19.3%), anorexia (<span class="stix">∼</span>17.1%), sore throat or pharyngalgia (<span class="stix">∼</span>11.1–16.2%), chill (<span class="stix">∼</span>15.0%), headache (<span class="stix">∼</span>9.4–14.0%), dizziness or confusion (<span class="stix">∼</span>7.6–9.2%), rhinorrhoea (<span class="stix">∼</span>3.5–9.2%), diarrhea (<span class="stix">∼</span>4.8–8.4%), nausea or vomiting (<span class="stix">∼</span>3.6–6.5%), abdominal pain (<span class="stix">∼</span>5.1%), nasal congestion (<span class="stix">∼</span>1.8–4.9%), and hemoptysis (<span class="stix">∼</span>2.0%).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Lai, C. C., Shih, T. P., Ko, W. C., Tang, H. J. & Hsueh, P. R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. Int. J. Antimicrob. Agents 55, 105924 (2020)." href="/articles/s41392-021-00736-8#ref-CR2" id="ref-link-section-d5157390e2830">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020)." href="/articles/s41392-021-00736-8#ref-CR3" id="ref-link-section-d5157390e2833">3</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Nascimento, V. A. D. et al. Genomic and phylogenetic characterisation of an imported case of SARS-CoV-2 in Amazonas State, Brazil. Mem. Inst. Oswaldo Cruz 115, e200310 (2020)." href="/articles/s41392-021-00736-8#ref-CR19" id="ref-link-section-d5157390e2836">19</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Jutzeler, C. R. et al. Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: a systematic review and meta-analysis. Travel Med. Infect. Dis. 37, 101825 (2020)." href="#ref-CR21" id="ref-link-section-d5157390e2839">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Pormohammad, A. et al. Clinical characteristics, laboratory findings, radiographic signs and outcomes of 61,742 patients with confirmed COVID-19 infection: a systematic review and meta-analysis. Microb. Pathog. 147, 104390 (2020)." href="#ref-CR22" id="ref-link-section-d5157390e2839_1">22</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wang, C., Horby, P. W., Hayden, F. G. & Gao, G. F. A novel coronavirus outbreak of global health concern. Lancet 395, 470–473 (2020)." href="#ref-CR23" id="ref-link-section-d5157390e2839_2">23</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Shu, T. et al. Plasma proteomics identify biomarkers and pathogenesis of COVID-19. Immunity 53, 1108–1122.e5 (2020)." href="#ref-CR24" id="ref-link-section-d5157390e2839_3">24</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Fu, L. et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J. Infect. 80, 656–665 (2020)." href="#ref-CR25" id="ref-link-section-d5157390e2839_4">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wong, C. K. H., Wong, J. Y. H., Tang, E. H. M., Au, C. H. & Wai, A. K. C. Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis. Sci. Rep. 10, 19765 (2020)." href="#ref-CR26" id="ref-link-section-d5157390e2839_5">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Yang, J. et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int. J. Infect. Dis. 94, 91–95 (2020)." href="#ref-CR27" id="ref-link-section-d5157390e2839_6">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Li, L. Q. et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J. Med. Virol. 92, 577–583 (2020)." href="#ref-CR28" id="ref-link-section-d5157390e2839_7">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Ghayda, R. A. et al. Correlations of clinical and laboratory characteristics of COVID-19: a systematic review and meta-analysis. Int. J. Environ. Res. Public Health 17, 5026 (2020)." href="#ref-CR29" id="ref-link-section-d5157390e2839_8">29</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Chua, T. H., Xu, Z. & King, N. K. K. Neurological manifestations in COVID-19: a systematic review and meta-analysis. Brain Inj. 34, 1549–1568 (2020)." href="#ref-CR30" id="ref-link-section-d5157390e2839_9">30</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Makhoul, K. & Jankovic, J. Parkinson’s disease after COVID-19. J. Neurol. Sci. 422, 117331 (2021)." href="/articles/s41392-021-00736-8#ref-CR31" id="ref-link-section-d5157390e2842">31</a></sup> Some patients (usually those with advanced age and comorbidities) may rapidly progress to viral pneumonia, life-threatening acute respiratory distress syndrome, or multiple organ failures.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Singhal, T. A review of coronavirus disease-2019 (COVID-19). Indian J. Pediatr. 87, 281–286 (2020)." href="/articles/s41392-021-00736-8#ref-CR32" id="ref-link-section-d5157390e2846">32</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Harrison, A. G., Lin, T. & Wang, P. Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol. 41, 1100–1115 (2020)." href="/articles/s41392-021-00736-8#ref-CR33" id="ref-link-section-d5157390e2849">33</a></sup> In addition to the respiratory tract and lungs being primarily affected, other organs and systems such as the heart, blood vessels, gastrointestinal tract, liver, kidneys, skin, and nervous systems, can be adversely involved.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Hossain, M. F. et al. COVID-19 outbreak: pathogenesis, current therapies, and potentials for future management. Front. Pharm. 11, 563478 (2020)." href="/articles/s41392-021-00736-8#ref-CR34" id="ref-link-section-d5157390e2853">34</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Simoneau, C. R. & Ott, M. Modeling multi-organ infection by SARS-CoV-2 using stem cell technology. Cell Stem Cell 27, 859–868 (2020)." href="/articles/s41392-021-00736-8#ref-CR35" id="ref-link-section-d5157390e2856">35</a></sup> Common laboratory abnormalities in COVID-19 patients are decreased albumin (<span class="stix">∼</span>43.0–60.6%), increased C-reactive protein (<span class="stix">∼</span>44.3–87.0%), D-dimer (<span class="stix">∼</span>29.3–48.0%), aspartate aminotransferase (<span class="stix">∼</span>18.6–47.0%), glucose (<span class="stix">∼</span>45.0%), procalcitonin (<span class="stix">∼</span>18.6–36.0%), creatine kinase (<span class="stix">∼</span>10.8–32.0%), troponin I/troponin T (<span class="stix">∼</span>29.0%), alanine aminotransferase (<span class="stix">∼</span>14.2–28.9%), total bilirubin (<span class="stix">∼</span>10.7–14.3%), and creatinine (<span class="stix">∼</span>3.1–11.0%), and decreased or increased lactate dehydrogenase (<span class="stix">∼</span>57.0% ↓ vs <span class="stix">∼</span>28.3–69.0% ↑), lymphocytes (<span class="stix">∼</span>57.4–68.0% ↓ vs <span class="stix">∼</span>8.2% ↑), neutrophils (<span class="stix">∼</span>3.6–9.0% ↓ vs <span class="stix">∼</span>25.9–31.0% ↑), leukocytes (<span class="stix">∼</span>20.1–29.4% ↓ vs <span class="stix">∼</span>9.8–22.0% ↑), and platelets (<span class="stix">∼</span>11.4–20.0% ↓ vs <span class="stix">∼</span>6.0% ↑).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Fu, L. et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J. Infect. 80, 656–665 (2020)." href="/articles/s41392-021-00736-8#ref-CR25" id="ref-link-section-d5157390e2861">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Li, L. Q. et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. J. Med. Virol. 92, 577–583 (2020)." href="/articles/s41392-021-00736-8#ref-CR28" id="ref-link-section-d5157390e2864">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Ghayda, R. A. et al. Correlations of clinical and laboratory characteristics of COVID-19: a systematic review and meta-analysis. Int. J. Environ. Res. Public Health 17, 5026 (2020)." href="/articles/s41392-021-00736-8#ref-CR29" id="ref-link-section-d5157390e2867">29</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Hu, J. & Wang, Y. The clinical characteristics and risk factors of severe COVID-19. Gerontology 6, 1–12 (2021)." href="/articles/s41392-021-00736-8#ref-CR36" id="ref-link-section-d5157390e2870">36</a></sup> Chest computed tomography (CT) scans revealed ground-glass opacity (<span class="stix">∼</span>64.6–91.2%), lesions consistent with bilateral (<span class="stix">∼</span>64.6–73.2%) or unilateral (<span class="stix">∼</span>21.3–25.3%) pneumonia, vascular changes (<span class="stix">∼</span>62.9–74.0%), air bronchogram (<span class="stix">∼</span>39.7–50.5%), bilateral or local patchy shadowing (<span class="stix">∼</span>43.0%, ~36.5%), halo sign (<span class="stix">∼</span>27.3%), solid nodules (<span class="stix">∼</span>5.2–20.7%), septal thickening (<span class="stix">∼</span>6.5–55.0%), interstitial abnormalities (<span class="stix">∼</span>14.1%), crazy paving pattern (<span class="stix">∼</span>15.0–32.0%), consolidation (<span class="stix">∼</span>27.7–73.5%), bronchial wall thickening (<span class="stix">∼</span>19.4–24.0%), fibrous stripes (<span class="stix">∼</span>25.9–37.2%), spider web design (<span class="stix">∼</span>22.3%), subpleural lines (<span class="stix">∼</span>15.0–28.0%), pleural effusion (<span class="stix">∼</span>3.0–7.8%), intrathoracic lymph node enlargement (<span class="stix">∼</span>3.0–5.3%), and pericardial effusion (<span class="stix">∼</span>3.0%).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Jutzeler, C. R. et al. Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: a systematic review and meta-analysis. Travel Med. Infect. Dis. 37, 101825 (2020)." href="/articles/s41392-021-00736-8#ref-CR21" id="ref-link-section-d5157390e2874">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Pormohammad, A. et al. Clinical characteristics, laboratory findings, radiographic signs and outcomes of 61,742 patients with confirmed COVID-19 infection: a systematic review and meta-analysis. Microb. Pathog. 147, 104390 (2020)." href="/articles/s41392-021-00736-8#ref-CR22" id="ref-link-section-d5157390e2877">22</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Fu, L. et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J. Infect. 80, 656–665 (2020)." href="/articles/s41392-021-00736-8#ref-CR25" id="ref-link-section-d5157390e2880">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kronbichler, A. et al. Asymptomatic patients as a source of COVID-19 infections: a systematic review and meta-analysis. Int. J. Infect. Dis. 98, 180–186 (2020)." href="#ref-CR37" id="ref-link-section-d5157390e2883">37</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wan, S. et al. CT manifestations and clinical characteristics of 1115 patients with coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Acad. Radiol. 27, 910–921 (2020)." href="#ref-CR38" id="ref-link-section-d5157390e2883_1">38</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Yang, H., Lan, Y., Yao, X., Lin, S. & Xie, B. The chest CT features of coronavirus disease 2019 (COVID-19) in China: a meta-analysis of 19 retrospective studies. Virol. J. 17, 159 (2020)." href="#ref-CR39" id="ref-link-section-d5157390e2883_2">39</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Muhammad, S. Z. et al. Chest computed tomography findings in hospitalized COVID-19 patients: a systematic review and meta-analysis. Infez. Med. 28, 295–301 (2020)." href="/articles/s41392-021-00736-8#ref-CR40" id="ref-link-section-d5157390e2886">40</a></sup></p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Fig. 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41392-021-00736-8/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-021-00736-8/MediaObjects/41392_2021_736_Fig2_HTML.png?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-021-00736-8/MediaObjects/41392_2021_736_Fig2_HTML.png" alt="figure 2" loading="lazy" width="685" height="624"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>Overview of clinical characteristics of COVID-19. CRP C-reactive protein, AST aspartate aminotransferase, PCT procalcitonin, TnI/TnT troponin I/troponin T, ALT alanine aminotransferase, LDH lactate dehydrogenase, CT computed tomography, GGO ground-glass opacity</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41392-021-00736-8/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></section><section data-title="The causative pathogen, SARS-CoV-2"><div class="c-article-section" id="Sec3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec3">The causative pathogen, SARS-CoV-2</h2><div class="c-article-section__content" id="Sec3-content"><p>SARS-CoV-2 is an enveloped, non-segmented, positive-sense single-stranded RNA virus with 29,903 nucleotides in its genome sequence containing 5′ capped and 3′ polyadenylated.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020)." href="#ref-CR41" id="ref-link-section-d5157390e2914">41</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020)." href="#ref-CR42" id="ref-link-section-d5157390e2914_1">42</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Khomari, F., Nabi-Afjadi, M., Yarahmadi, S., Eskandari, H. & Bahreini, E. Effects of cell proteostasis network on the survival of SARS-CoV-2. Biol. Proced. Online 23, 8 (2021)." href="/articles/s41392-021-00736-8#ref-CR43" id="ref-link-section-d5157390e2917">43</a></sup> The 5′ two-thirds region of the genome is occupied by two large open reading frames (ORFs), ORF1a and ORF1b, that encodes 15–16 nonstructural proteins.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="V’kovski, P., Kratzel, A., Steiner, S., Stalder, H. & Thiel, V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat. Rev. Microbiol. 19, 155–170 (2021)." href="/articles/s41392-021-00736-8#ref-CR44" id="ref-link-section-d5157390e2921">44</a></sup> Other functional ORFs encode structural and accessory proteins.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Bzówka, M. et al. Structural and evolutionary analysis indicate that the SARS-CoV-2 Mpro is a challenging target for small-molecule inhibitor design. Int. J. Mol. Sci. 21, 3099 (2020)." href="/articles/s41392-021-00736-8#ref-CR45" id="ref-link-section-d5157390e2925">45</a></sup> The structural proteins include the distinctive spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins, among which the S, E, and M proteins compose the envelope structure, while the N protein encapsulates the viral genome.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Adedokun, K. A., Olarinmoye, A. O., Mustapha, J. O. & Kamorudeen, R. T. A close look at the biology of SARS-CoV-2, and the potential influence of weather conditions and seasons on COVID-19 case spread. Infect. Dis. Poverty 9, 77 (2020)." href="/articles/s41392-021-00736-8#ref-CR46" id="ref-link-section-d5157390e2929">46</a></sup> SARS-CoV-2 is generally spherical with some pleomorphism and a diameter of <span class="stix">∼</span>60–140 nm.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020)." href="/articles/s41392-021-00736-8#ref-CR3" id="ref-link-section-d5157390e2933">3</a></sup> The viral-enveloped lipid bilayer consists of cholesterols and phospholipids, which makes the virus susceptible to dry heat, detergents, and organic solvents.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Adedokun, K. A., Olarinmoye, A. O., Mustapha, J. O. & Kamorudeen, R. T. A close look at the biology of SARS-CoV-2, and the potential influence of weather conditions and seasons on COVID-19 case spread. Infect. Dis. Poverty 9, 77 (2020)." href="/articles/s41392-021-00736-8#ref-CR46" id="ref-link-section-d5157390e2938">46</a></sup> This novel coronavirus was assigned to the genus <i>Betacoronavirus</i> in the family <i>Coronaviridae</i> of the order <i>Nidovirales</i> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41392-021-00736-8#Fig3">3</a>).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Rahimi, A., Mirzazadeh, A. & Tavakolpour, S. Genetics and genomics of SARS-CoV-2: a review of the literature with the special focus on genetic diversity and SARS-CoV-2 genome detection. Genomics 113, 1221–1232 (2021)." href="/articles/s41392-021-00736-8#ref-CR18" id="ref-link-section-d5157390e2954">18</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020)." href="/articles/s41392-021-00736-8#ref-CR42" id="ref-link-section-d5157390e2957">42</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Chen, L. et al. RNA based mNGS approach identifies a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan outbreak. Emerg. Microbes Infect. 9, 313–319 (2020)." href="/articles/s41392-021-00736-8#ref-CR47" id="ref-link-section-d5157390e2960">47</a></sup> SARS-CoV-2 has a 96.2% identity throughout the genome to RaTG13, a bat-borne coronavirus in <i>Rhinolophus affinis.</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020)." href="/articles/s41392-021-00736-8#ref-CR48" id="ref-link-section-d5157390e2967">48</a></sup> Droplet, aerosol, contact, fecal–oral and transplacental transmissions are documented human-to-human transmission routes.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Shereen, M. A., Khan, S., Kazmi, A., Bashir, N. & Siddique, R. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. J. Adv. Res. 24, 91–98 (2020)." href="#ref-CR49" id="ref-link-section-d5157390e2971">49</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Morawska, L. & Milton, D. K. It is time to address airborne transmission of coronavirus disease 2019 (COVID-19). Clin. Infect. Dis. 71, 2311–2313 (2020)." href="#ref-CR50" id="ref-link-section-d5157390e2971_1">50</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Jin, Y. H. et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil. Med. Res. 7, 4 (2020)." href="#ref-CR51" id="ref-link-section-d5157390e2971_2">51</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wang, Z. et al. Transmission and prevention of SARS-CoV-2. Biochem. Soc. Trans. 48, 2307–2316 (2020)." href="#ref-CR52" id="ref-link-section-d5157390e2971_3">52</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Vivanti, A. J. et al. Transplacental transmission of SARS-CoV-2 infection. Nat. Commun. 11, 3572 (2020)." href="/articles/s41392-021-00736-8#ref-CR53" id="ref-link-section-d5157390e2974">53</a></sup> Small droplets with SARS-CoV-2 can travel tens of meters in favorable atmospheric conditions and remain viable and infectious from 3 h to days.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Singhal, T. A review of coronavirus disease-2019 (COVID-19). Indian J. Pediatr. 87, 281–286 (2020)." href="/articles/s41392-021-00736-8#ref-CR32" id="ref-link-section-d5157390e2978">32</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Khalaf, K. et al. SARS-CoV-2: pathogenesis, and advancements in diagnostics and treatment. Front. Immunol. 11, 570927 (2020)." href="/articles/s41392-021-00736-8#ref-CR54" id="ref-link-section-d5157390e2981">54</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Morawska, L. & Cao, J. Airborne transmission of SARS-CoV-2: the world should face the reality. Environ. Int. 139, 105730 (2020)." href="/articles/s41392-021-00736-8#ref-CR55" id="ref-link-section-d5157390e2984">55</a></sup> Patients mildly affected and asymptomatic carriers constituting the majority of COVID-19 cases are thought to be primarily responsible for the spread of SARS-CoV-2.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Ikitimur, H. et al. Determining host factors contributing to disease severity in a family cluster of 29 hospitalized SARS-CoV-2 patients: could genetic factors be relevant in the clinical course of COVID-19? J. Med. Virol. 93, 357–365 (2021)." href="/articles/s41392-021-00736-8#ref-CR10" id="ref-link-section-d5157390e2988">10</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Bai, Y. et al. Presumed asymptomatic carrier transmission of COVID-19. JAMA 323, 1406–1407 (2020)." href="/articles/s41392-021-00736-8#ref-CR56" id="ref-link-section-d5157390e2991">56</a></sup></p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Fig. 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/s41392-021-00736-8/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-021-00736-8/MediaObjects/41392_2021_736_Fig3_HTML.png?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-021-00736-8/MediaObjects/41392_2021_736_Fig3_HTML.png" alt="figure 3" loading="lazy" width="685" height="486"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>The causative pathogen, SARS-CoV-2. <b>a</b> The taxonomy of SARS-CoV-2 is shown (from <a href="https://talk.ictvonline.org/taxonomy/">https://talk.ictvonline.org/taxonomy/</a>). <b>b</b> SARS-CoV-2 is ssRNA virus with a diameter of ~60–140 nm and whole viral genome sequence of 29,903 nucleotides, and possesses distinctive S protein; 96.2% identity is shown between SARS-CoV-2 and a bat-borne coronavirus, RaTG13. SARS-CoV-2 spreads from human to human via droplet, aerosol, contact, fecal–oral, and transplacental transmissions. Droplets with SARS-CoV-2 can spread up to tens of meters and remain viable and infectious for 3 h to days. SARS-CoV-2 severe acute respiratory coronavirus 2, S spike protein, ssRNA single-strand RNA</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/s41392-021-00736-8/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>As of 17 May 2021, the worldwide circulating SARS-CoV-2 variants mainly include the B.1.1.7 (63%), B.1.617.2 (22%), P.1 (6%), B.1.526 (2%), and others (<a href="https://covid19dashboard.regeneron.com">https://covid19dashboard.regeneron.com</a>). Lineage B.1.1.7 first detected in the United Kingdom in September 2020 has 21 characteristic mutations and exists in comparative transmission effectivity.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Frampton, D. et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. Lancet Infect. Dis. 21, 1246–1256 (2021)." href="/articles/s41392-021-00736-8#ref-CR57" id="ref-link-section-d5157390e3035">57</a></sup> Among the S protein mutations, the N501Y substitution would change the receptor-binding domain conformation and may slightly increase 18% of fatality risk. Mutation del69–70, considered to be responsible for stronger viral transmissibility, may cause S-gene target failure and produce a positive result for other targets at real-time reverse transcription-polymerase chain reaction assays, which could be a proxy for diagnosing B.1.1.7 infections.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Zhao, S. et al. Inferring the association between the risk of COVID-19 case fatality and N501Y substitution in SARS-CoV-2. Viruses 13, 638 (2021)." href="/articles/s41392-021-00736-8#ref-CR58" id="ref-link-section-d5157390e3039">58</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Galloway, S. E. et al. Emergence of SARS-CoV-2 B.1.1.7 lineage-United States, December 29, 2020-January 12, 2021. MMWR Morb. Mortal. Wkly. Rep. 70, 95–99 (2021)." href="/articles/s41392-021-00736-8#ref-CR59" id="ref-link-section-d5157390e3042">59</a></sup> Other two S protein substitutions, E484K in some strains of B.1.1.7 and L452R in B.1.617.2, may lead to much poorer effectivity of specific monoclonal antibody treatment in the corresponding infected cases (<a href="https://www.cdc.gov">https://www.cdc.gov</a>).</p></div></div></section><section data-title="Pathogenesis of SARS-CoV-2"><div class="c-article-section" id="Sec4-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec4">Pathogenesis of SARS-CoV-2</h2><div class="c-article-section__content" id="Sec4-content"><h3 class="c-article__sub-heading" id="Sec5">Entry and replication of SARS-CoV-2</h3><p>Cell entry of SARS-CoV-2 depends on two determinants: (1) the viral S protein recognizes ACE2 receptor and (2) TMPRSS2 primes S protein.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Wang, Q. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181, 894–904.e9 (2020)." href="/articles/s41392-021-00736-8#ref-CR60" id="ref-link-section-d5157390e3065">60</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8 (2020)." href="/articles/s41392-021-00736-8#ref-CR61" id="ref-link-section-d5157390e3068">61</a></sup> The S1 subunit of the envelope-embedded S glycoprotein attaches to the cellular ACE2 receptor via the polar contacts of hydrophilic residues.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Wang, Q. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181, 894–904.e9 (2020)." href="/articles/s41392-021-00736-8#ref-CR60" id="ref-link-section-d5157390e3072">60</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Li, F., Li, W., Farzan, M. & Harrison, S. C. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309, 1864–1868 (2005)." href="/articles/s41392-021-00736-8#ref-CR62" id="ref-link-section-d5157390e3075">62</a></sup> TMPRSS2 may trigger a proteolytic cleavage at the S1/S2 multibasic cleavage site.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Zipeto, D., Palmeira, J. D. F., Argañaraz, G. A. & Argañaraz, E. R. ACE2/ADAM17/TMPRSS2 interplay may be the main risk factor for COVID-19. Front. Immunol. 11, 576745 (2020)." href="/articles/s41392-021-00736-8#ref-CR63" id="ref-link-section-d5157390e3079">63</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Smatti, M. K., Al-Sarraj, Y. A., Albagha, O. & Yassine, H. M. Host genetic variants potentially associated with SARS-CoV-2: a multi-population analysis. Front. Genet. 11, 578523 (2020)." href="/articles/s41392-021-00736-8#ref-CR64" id="ref-link-section-d5157390e3082">64</a></sup> Other than ACE2, some studies reported that the human dipeptidyl peptidase 4 (DPP4), the cell-surface glucose-regulated protein-78, and the receptor tyrosine kinase anexelekto may also be conducive to viral entry and infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Liu, C., von Brunn, A. & Zhu, D. Cyclophilin A and CD147: novel therapeutic targets for the treatment of COVID-19. Med. Drug Discov. 7, 100056 (2020)." href="#ref-CR65" id="ref-link-section-d5157390e3086">65</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wang, S. et al. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Res. 31, 126–140 (2021)." href="#ref-CR66" id="ref-link-section-d5157390e3086_1">66</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Ibrahim, I. M., Abdelmalek, D. H., Elshahat, M. E. & Elfiky, A. A. COVID-19 spike-host cell receptor GRP78 binding site prediction. J. Infect. 80, 554–562 (2020)." href="#ref-CR67" id="ref-link-section-d5157390e3086_2">67</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Vankadari, N. & Wilce, J. A. Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg. Microbes Infect. 9, 601–604 (2020)." href="/articles/s41392-021-00736-8#ref-CR68" id="ref-link-section-d5157390e3089">68</a></sup> Cathepsin B/L and furin, paired basic amino acid cleaving enzyme (FURIN) may also catalyze S protein proteolytic cleavage.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Smatti, M. K., Al-Sarraj, Y. A., Albagha, O. & Yassine, H. M. Host genetic variants potentially associated with SARS-CoV-2: a multi-population analysis. Front. Genet. 11, 578523 (2020)." href="/articles/s41392-021-00736-8#ref-CR64" id="ref-link-section-d5157390e3093">64</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="Daniloski, Z. et al. Identification of required host factors for SARS-CoV-2 infection in human cells. Cell 184, 92–105.e16 (2021)." href="/articles/s41392-021-00736-8#ref-CR69" id="ref-link-section-d5157390e3096">69</a></sup> As the S protein is cleaved to the S1 and the S2 domain, the cell surface receptor neuropilin-1 (NRP1) may bind to the C-terminal functional furin-cleavage sequence of the S1 domain more strongly in some cases and help the S2 isolating from the S1 domain.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Latini, A. et al. COVID-19 and genetic variants of protein involved in the SARS-CoV-2 entry into the host cells. Genes 11, 1010 (2020)." href="/articles/s41392-021-00736-8#ref-CR70" id="ref-link-section-d5157390e3101">70</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 71" title="Li, Z. L. & Buck, M. Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of spike protein domains S1 and S2. Biophys. J. 120, 2828–2837 (2021)." href="/articles/s41392-021-00736-8#ref-CR71" id="ref-link-section-d5157390e3104">71</a></sup> After S1 detachment, the S2 subunit undergoes a conformational change and mediates the fusion between the virus and the host membranes to mediate viral infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 71" title="Li, Z. L. & Buck, M. Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of spike protein domains S1 and S2. Biophys. J. 120, 2828–2837 (2021)." href="/articles/s41392-021-00736-8#ref-CR71" id="ref-link-section-d5157390e3108">71</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Verdecchia, P., Cavallini, C., Spanevello, A. & Angeli, F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med. 76, 14–20 (2020)." href="/articles/s41392-021-00736-8#ref-CR72" id="ref-link-section-d5157390e3111">72</a></sup> The virus enters the cytoplasm and starts the replication process to assemble new viral particles and amplify its viral load.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="Daniloski, Z. et al. Identification of required host factors for SARS-CoV-2 infection in human cells. Cell 184, 92–105.e16 (2021)." href="/articles/s41392-021-00736-8#ref-CR69" id="ref-link-section-d5157390e3115">69</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Rodríguez, C. et al. Pulmonary endothelial dysfunction and thrombotic complications in COVID-19 patients. Am. J. Respir. Cell Mol. Biol. 64, 407–415 (2020)." href="/articles/s41392-021-00736-8#ref-CR73" id="ref-link-section-d5157390e3118">73</a></sup> During the viral entry and replication process, cyclophilin A is essential for viral replication and its interaction with CD147 may mediate SARS-CoV-2 entering the host cells.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Liu, C., von Brunn, A. & Zhu, D. Cyclophilin A and CD147: novel therapeutic targets for the treatment of COVID-19. Med. Drug Discov. 7, 100056 (2020)." href="/articles/s41392-021-00736-8#ref-CR65" id="ref-link-section-d5157390e3122">65</a></sup></p><h3 class="c-article__sub-heading" id="Sec6">Renin–angiotensin–aldosterone system (RAAS)</h3><p>RAAS is a complex system involved in multiple biological processes that are responsible for inducing a cascade of vasoactive peptides, which regulate vascular and renal functions.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Khalaf, K. et al. SARS-CoV-2: pathogenesis, and advancements in diagnostics and treatment. Front. Immunol. 11, 570927 (2020)." href="/articles/s41392-021-00736-8#ref-CR54" id="ref-link-section-d5157390e3133">54</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Vaduganathan, M. et al. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. N. Engl. J. Med. 382, 1653–1659 (2020)." href="/articles/s41392-021-00736-8#ref-CR74" id="ref-link-section-d5157390e3136">74</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Medina-Enríquez, M. M. et al. ACE2: the molecular doorway to SARS-CoV-2. Cell Biosci. 10, 148 (2020)." href="/articles/s41392-021-00736-8#ref-CR75" id="ref-link-section-d5157390e3139">75</a></sup> In the blood, the precursor angiotensinogen (AGT) is hydrolyzed to angiotensin I (Ang I) by the active renin.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="Warner, F. J., Smith, A. I., Hooper, N. M. & Turner, A. J. Angiotensin-converting enzyme-2: a molecular and cellular perspective. Cell Mol. Life Sci. 61, 2704–2713 (2004)." href="/articles/s41392-021-00736-8#ref-CR76" id="ref-link-section-d5157390e3143">76</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Bader, M. & Ganten, D. Update on tissue renin-angiotensin systems. J. Mol. Med. 86, 615–621 (2008)." href="/articles/s41392-021-00736-8#ref-CR77" id="ref-link-section-d5157390e3146">77</a></sup> In the lungs, ACE removes the C-terminal dipeptide of Ang I to produce a potent vasoconstrictor, Ang II, which promotes detrimental effects by acting on Ang II type 1 receptor (AT1R).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Donoghue, M. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ. Res. 87, e1–e9 (2000)." href="#ref-CR78" id="ref-link-section-d5157390e3150">78</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Patel, V. B., Zhong, J. C., Grant, M. B. & Oudit, G. Y. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ. Res. 118, 1313–1326 (2016)." href="#ref-CR79" id="ref-link-section-d5157390e3150_1">79</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 80" title="Sieńko, J. et al. COVID-19: the influence of ACE genotype and ACE-I and ARBs on the course of SARS-CoV-2 infection in elderly patients. Clin. Inter. Aging 15, 1231–1240 (2020)." href="/articles/s41392-021-00736-8#ref-CR80" id="ref-link-section-d5157390e3153">80</a></sup> ACE2 removes a single C-terminal amino acid from Ang I and Ang II to generate Ang-(1–9) and Ang-(1–7), of which the former is in turn converted to Ang-(1–7) by ACE.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 81" title="Hamming, I. et al. The emerging role of ACE2 in physiology and disease. J. Pathol. 212, 1–11 (2007)." href="/articles/s41392-021-00736-8#ref-CR81" id="ref-link-section-d5157390e3157">81</a></sup> Ang-(1–7) counters Ang II cellular and molecular effects by binding and activating the G-protein-coupled Mas receptor (MasR).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 79" title="Patel, V. B., Zhong, J. C., Grant, M. B. & Oudit, G. Y. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ. Res. 118, 1313–1326 (2016)." href="/articles/s41392-021-00736-8#ref-CR79" id="ref-link-section-d5157390e3161">79</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Haitao, T. et al. COVID-19 and sex differences: mechanisms and biomarkers. Mayo Clin. Proc. 95, 2189–2203 (2020)." href="/articles/s41392-021-00736-8#ref-CR82" id="ref-link-section-d5157390e3164">82</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Burrell, L. M., Johnston, C. I., Tikellis, C. & Cooper, M. E. ACE2, a new regulator of the renin-angiotensin system. Trends Endocrinol. Metab. 15, 166–169 (2004)." href="/articles/s41392-021-00736-8#ref-CR83" id="ref-link-section-d5157390e3167">83</a></sup> ACE2 catalytic efficiency with Ang II as a substrate is 400-fold higher than with Ang I.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Burrell, L. M., Johnston, C. I., Tikellis, C. & Cooper, M. E. ACE2, a new regulator of the renin-angiotensin system. Trends Endocrinol. Metab. 15, 166–169 (2004)." href="/articles/s41392-021-00736-8#ref-CR83" id="ref-link-section-d5157390e3172">83</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Vickers, C. et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J. Biol. Chem. 277, 14838–14843 (2002)." href="/articles/s41392-021-00736-8#ref-CR84" id="ref-link-section-d5157390e3175">84</a></sup> Accordingly, ACE2, an ACE homolog, is a key negative regulator antagonizing the activation of the classical RAAS by counterbalancing ACE actions.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Haitao, T. et al. COVID-19 and sex differences: mechanisms and biomarkers. Mayo Clin. Proc. 95, 2189–2203 (2020)." href="/articles/s41392-021-00736-8#ref-CR82" id="ref-link-section-d5157390e3179">82</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Cheng, H., Wang, Y. & Wang, G. Q. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. J. Med. Virol. 92, 726–730 (2020)." href="/articles/s41392-021-00736-8#ref-CR85" id="ref-link-section-d5157390e3182">85</a></sup> ACE and ACE2 maintain the homeostasis via the “adverse” ACE/Ang II/AT1R axis and the “protective” ACE2/Ang-(1–7)/MasR axis. In general, ACE/ACE2 imbalance contributes to RAAS overactivation and pulmonary shutdown, and a high ACE activity and a reduced <i>ACE2</i> expression would increase the risk of pulmonary and cardiovascular diseases.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 86" title="Yamamoto, N. et al. SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype. Gene 758, 144944 (2020)." href="/articles/s41392-021-00736-8#ref-CR86" id="ref-link-section-d5157390e3189">86</a></sup> ACE2 mainly binds to cell membranes and rarely exists in a circulating soluble form.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Verdecchia, P., Cavallini, C., Spanevello, A. & Angeli, F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med. 76, 14–20 (2020)." href="/articles/s41392-021-00736-8#ref-CR72" id="ref-link-section-d5157390e3193">72</a></sup> Continued viral infection and replication markedly downregulate ACE2 receptors, leading to the loss of the catalytic effect of membrane ACE2, and thus results in unopposed acute Ang II aggregation and local RAAS activation.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Vaduganathan, M. et al. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. N. Engl. J. Med. 382, 1653–1659 (2020)." href="/articles/s41392-021-00736-8#ref-CR74" id="ref-link-section-d5157390e3197">74</a></sup> During ACE2 downregulation, an accentuating RAAS imbalance may further exacerbate pathophysiological alteration in COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Cheng, H., Wang, Y. & Wang, G. Q. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. J. Med. Virol. 92, 726–730 (2020)." href="/articles/s41392-021-00736-8#ref-CR85" id="ref-link-section-d5157390e3202">85</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Arnold, R. H. COVID-19-does this disease kill due to imbalance of the renin angiotensin system (RAS) caused by genetic and gender differences in the response to viral ACE2 attack? Heart Lung Circ. 29, 964–972 (2020)." href="/articles/s41392-021-00736-8#ref-CR87" id="ref-link-section-d5157390e3205">87</a></sup></p><h3 class="c-article__sub-heading" id="Sec7">Immunopathogenesis</h3><p>SARS-CoV-2 activates innate and acquired immune response, and further impairs the immune system and causes cytokine storm, which is an uncontrolled inflammatory response with elevations of circulating cytokine levels.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Rodríguez, C. et al. Pulmonary endothelial dysfunction and thrombotic complications in COVID-19 patients. Am. J. Respir. Cell Mol. Biol. 64, 407–415 (2020)." href="/articles/s41392-021-00736-8#ref-CR73" id="ref-link-section-d5157390e3216">73</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Mangalmurti, N. & Hunter, C. A. Cytokine storms: understanding COVID-19. Immunity 53, 19–25 (2020)." href="/articles/s41392-021-00736-8#ref-CR88" id="ref-link-section-d5157390e3219">88</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Yang, L. et al. COVID-19: immunopathogenesis and immunotherapeutics. Signal Transduct. Target. Ther. 5, 128 (2020)." href="/articles/s41392-021-00736-8#ref-CR89" id="ref-link-section-d5157390e3222">89</a></sup> The initial antiviral responses are promoted by pattern recognition receptors (PRRs) detecting pathogen-associated molecular patterns (PAMPs).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 90" title="Molaei, S., Dadkhah, M., Asghariazar, V., Karami, C. & Safarzadeh, E. The immune response and immune evasion characteristics in SARS-CoV, MERS-CoV, and SARS-CoV-2: vaccine design strategies. Int. Immunopharmacol. 92, 107051 (2021)." href="/articles/s41392-021-00736-8#ref-CR90" id="ref-link-section-d5157390e3226">90</a></sup> Retinoic acid-inducible gene I (RIG-I) is an interferon (IFN)-stimulated gene (ISG), and RIG-I-mediated signaling could promote induction of antiviral IFN responses.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 90" title="Molaei, S., Dadkhah, M., Asghariazar, V., Karami, C. & Safarzadeh, E. The immune response and immune evasion characteristics in SARS-CoV, MERS-CoV, and SARS-CoV-2: vaccine design strategies. Int. Immunopharmacol. 92, 107051 (2021)." href="/articles/s41392-021-00736-8#ref-CR90" id="ref-link-section-d5157390e3230">90</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Mohamed Khosroshahi, L., Rokni, M., Mokhtari, T. & Noorbakhsh, F. Immunology, immunopathogenesis and immunotherapeutics of COVID-19; an overview. Int. Immunopharmacol. 93, 107364 (2021)." href="/articles/s41392-021-00736-8#ref-CR91" id="ref-link-section-d5157390e3233">91</a></sup> Recognition of virus promotes downstream transduction in nuclear factor-κB, IFN regulatory factor-3, and Janus kinase-signal transducer and activator of transcription signaling pathways.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Catanzaro, M. et al. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct. Target. Ther. 5, 84 (2020)." href="/articles/s41392-021-00736-8#ref-CR92" id="ref-link-section-d5157390e3237">92</a></sup> Innate immune cells, such as parenchymal cells, neutrophils, dendritic cells, and macrophages, are stimulated to secrete inflammatory mediators.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Ebrahimi, N. et al. Recent findings on the coronavirus disease 2019 (COVID-19); immunopathogenesis and immunotherapeutics. Int. Immunopharmacol. 89, 107082 (2020)." href="/articles/s41392-021-00736-8#ref-CR93" id="ref-link-section-d5157390e3241">93</a></sup> SARS-CoV-2 disturbs the immune system with its immune evasion strategies, in which viral PAMPs escape from the detection of cytosolic PRRs efficiently.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Kumar, S., Nyodu, R., Maurya, V. K. & Saxena, S. K. in Coronavirus Disease 2019 (COVID-19): Epidemiology, Pathogenesis, Diagnosis, and Therapeutics (ed. Saxena, S. K.) Ch. 5 (Springer Singapore, 2020)." href="/articles/s41392-021-00736-8#ref-CR94" id="ref-link-section-d5157390e3246">94</a></sup> The virus weakens the antiviral effects of ISG products through dysregulating IFN signaling and IFN generation.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Kumar, S., Nyodu, R., Maurya, V. K. & Saxena, S. K. in Coronavirus Disease 2019 (COVID-19): Epidemiology, Pathogenesis, Diagnosis, and Therapeutics (ed. Saxena, S. K.) Ch. 5 (Springer Singapore, 2020)." href="/articles/s41392-021-00736-8#ref-CR94" id="ref-link-section-d5157390e3250">94</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Schurr, T. G. Host genetic factors and susceptibility to SARS-CoV-2 infection. Am. J. Hum. Biol. 32, e23497 (2020)." href="/articles/s41392-021-00736-8#ref-CR95" id="ref-link-section-d5157390e3253">95</a></sup> In acquired immunity, SARS-CoV-2 may target the CD147 spike protein of T lymphocytes.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Azkur, A. K. et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 75, 1564–1581 (2020)." href="/articles/s41392-021-00736-8#ref-CR96" id="ref-link-section-d5157390e3257">96</a></sup> Viral peptides are presented by major histocompatibility complex (MHC) Class-I molecules to CD8<sup>+</sup> T cells (cytotoxic T cells) to kill the virus directly, while by MHC Class-II molecules to CD4<sup>+</sup> T cells (helper T cells).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Azkur, A. K. et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 75, 1564–1581 (2020)." href="/articles/s41392-021-00736-8#ref-CR96" id="ref-link-section-d5157390e3265">96</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 97" title="Dhama, K. et al. An update on SARS-CoV-2/COVID-19 with particular reference to its clinical pathology, pathogenesis, immunopathology and mitigation strategies. Travel Med. Infect. Dis. 37, 101755 (2020)." href="/articles/s41392-021-00736-8#ref-CR97" id="ref-link-section-d5157390e3268">97</a></sup> CD4<sup>+</sup> T cells generate proinflammatory cytokines and mediators to facilitate other immune cells.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Mangalmurti, N. & Hunter, C. A. Cytokine storms: understanding COVID-19. Immunity 53, 19–25 (2020)." href="/articles/s41392-021-00736-8#ref-CR88" id="ref-link-section-d5157390e3275">88</a></sup> B lymphocytes are directly stimulated by SARS-CoV-2 and interact with CD4<sup>+</sup> T cells to produce substantial immunoglobulin G antibodies, which lead to the disruption of the virus and increased proinflammatory cytokines.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Agrawal, H. et al. An assessment on impact of COVID-19 infection in a gender specific manner. Stem Cell Rev. Rep. 17, 94–112 (2021)." href="/articles/s41392-021-00736-8#ref-CR14" id="ref-link-section-d5157390e3281">14</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Azkur, A. K. et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. Allergy 75, 1564–1581 (2020)." href="/articles/s41392-021-00736-8#ref-CR96" id="ref-link-section-d5157390e3284">96</a></sup> Complement activation through classical or alternative pathways generates a number of chemotactic/inflammatory mediators.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Mohamed Khosroshahi, L., Rokni, M., Mokhtari, T. & Noorbakhsh, F. Immunology, immunopathogenesis and immunotherapeutics of COVID-19; an overview. Int. Immunopharmacol. 93, 107364 (2021)." href="/articles/s41392-021-00736-8#ref-CR91" id="ref-link-section-d5157390e3288">91</a></sup> The release of proinflammatory cytokines also could be induced by increased A disintegrin and metalloproteinase 17 activity due to viral invasion.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Haitao, T. et al. COVID-19 and sex differences: mechanisms and biomarkers. Mayo Clin. Proc. 95, 2189–2203 (2020)." href="/articles/s41392-021-00736-8#ref-CR82" id="ref-link-section-d5157390e3292">82</a></sup> The cytokine storm, which is characterized by a radical rise in the number of inflammatory cytokines/chemokines such as interleukin-2 (IL-2), IL-6, IL-7, IL-10, granulocyte-colony stimulating factor, IFN-γ-inducible protein 10, tumor necrosis factor-α, macrophage inflammatory protein-1α, monocyte chemoattractant protein-1, C–X–C motif ligand 9 (CXCL9), CXCL10, and CXCL11, triggers extensive tissue injury and body dysfunction and is considered as the primary contribution to mortality in COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Singhal, T. A review of coronavirus disease-2019 (COVID-19). Indian J. Pediatr. 87, 281–286 (2020)." href="/articles/s41392-021-00736-8#ref-CR32" id="ref-link-section-d5157390e3297">32</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Harrison, A. G., Lin, T. & Wang, P. Mechanisms of SARS-CoV-2 transmission and pathogenesis. Trends Immunol. 41, 1100–1115 (2020)." href="/articles/s41392-021-00736-8#ref-CR33" id="ref-link-section-d5157390e3300">33</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 97" title="Dhama, K. et al. An update on SARS-CoV-2/COVID-19 with particular reference to its clinical pathology, pathogenesis, immunopathology and mitigation strategies. Travel Med. Infect. Dis. 37, 101755 (2020)." href="/articles/s41392-021-00736-8#ref-CR97" id="ref-link-section-d5157390e3303">97</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Ramos-Lopez, O. et al. Exploring host genetic polymorphisms involved in SARS-CoV infection outcomes: implications for personalized medicine in COVID-19. Int. J. Genomics 2020, 6901217 (2020)." href="/articles/s41392-021-00736-8#ref-CR98" id="ref-link-section-d5157390e3306">98</a></sup> Among these inflammatory cytokines/chemokines, IL-6 was reported to play a key role in COVID-19 cytokine storm development.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Yang, L. et al. COVID-19: immunopathogenesis and immunotherapeutics. Signal Transduct. Target. Ther. 5, 128 (2020)." href="/articles/s41392-021-00736-8#ref-CR89" id="ref-link-section-d5157390e3310">89</a></sup> However, a study found that only one cytokine, macrophage migration inhibitory factor, was significantly higher in COVID-19 patients than healthy controls. In addition, elevations of IL-6 were only found in some severe/critical patients and much less than patients with other cytokine storm syndrome-associated diseases.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Syed, F. et al. Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19. J. Infect. Dis. 224, 60–69 (2021)." href="/articles/s41392-021-00736-8#ref-CR99" id="ref-link-section-d5157390e3314">99</a></sup> These controversial results pointed that SARS-CoV-2 causes a chemokine storm, not a cytokine storm, providing an interesting insight into COVID-19 immunopathogenesis.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Syed, F. et al. Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19. J. Infect. Dis. 224, 60–69 (2021)." href="/articles/s41392-021-00736-8#ref-CR99" id="ref-link-section-d5157390e3318">99</a></sup> Genetically determined individual differences in immunity may relate to both variants in the immune-related genes and the inherent differences in the X- and Y-chromosome gene expressions.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="von der Thüsen, J. & van der Eerden, M. Histopathology and genetic susceptibility in COVID-19 pneumonia. Eur. J. Clin. Invest. 50, e13259 (2020)." href="/articles/s41392-021-00736-8#ref-CR100" id="ref-link-section-d5157390e3322">100</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Gebhard, C., Regitz-Zagrosek, V., Neuhauser, H. K., Morgan, R. & Klein, S. L. Impact of sex and gender on COVID-19 outcomes in Europe. Biol. Sex Differ. 11, 29 (2020)." href="/articles/s41392-021-00736-8#ref-CR101" id="ref-link-section-d5157390e3325">101</a></sup></p></div></div></section><section data-title="Autosomal loci and genes associated with COVID-19"><div class="c-article-section" id="Sec8-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec8">Autosomal loci and genes associated with COVID-19</h2><div class="c-article-section__content" id="Sec8-content"><h3 class="c-article__sub-heading" id="Sec9">2q24.2 and the interferon induced with helicase C domain 1 gene (<i>IFIH1</i>)</h3><p>The IFIH1 protein is a primary PRR that first senses the coronavirus RNA and then triggers innate immunity and activates mitochondrial antiviral signaling protein.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Maiti, A. K. The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection. Immunogenetics 72, 387–391 (2020)." href="/articles/s41392-021-00736-8#ref-CR102" id="ref-link-section-d5157390e3345">102</a></sup> The variant rs1990760 (p.Ala946Thr) of the <i>IFIH1</i> gene has been reported to be positively related to increased expression of the viral resistance gene <i>IFIH1</i> and IFN-induced gene.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Molineros, J. E. et al. Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. PLoS Genet. 9, e1003222 (2013)." href="/articles/s41392-021-00736-8#ref-CR103" id="ref-link-section-d5157390e3355">103</a></sup> This polymorphic variant in various ethnic populations is correlated with population migration and originated from the European and Asian populations. It is expected that rs1990760 T-allele confers carriers more resistance to COVID-19, e.g., Africans and African-Americans with low-frequency ranging from 0.06 to 0.35 have a more vulnerable risk for COVID-19 than Caucasians and Indians with an overall frequency of 0.56.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Maiti, A. K. The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection. Immunogenetics 72, 387–391 (2020)." href="/articles/s41392-021-00736-8#ref-CR102" id="ref-link-section-d5157390e3359">102</a></sup></p><h3 class="c-article__sub-heading" id="Sec10">3p21.31</h3><p>A genome-wide association study (GWAS) conducted in Italy and Spain revealed that a 3p21.31 gene cluster comprised of the solute carrier protein family 6 member 20 gene (<i>SLC6A20</i>), the leucine zipper transcription factor like 1 gene (<i>LZTFL1</i>), the FYVE and coiled-coil domain autophagy adaptor 1 gene (<i>FYCO1</i>), the C–X–C motif chemokine receptor 6 gene (<i>CXCR6</i>), the X–C motif chemokine receptor 1 gene (<i>XCR1</i>), and the C-C motif chemokine receptor 9 gene (<i>CCR9</i>) is a genetically susceptible locus in severe COVID-19 patients with respiratory failure.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Ellinghaus, D. et al. Genomewide association study of severe COVID-19 with respiratory failure. N. Engl. J. Med. 383, 1522–1534 (2020)." href="/articles/s41392-021-00736-8#ref-CR104" id="ref-link-section-d5157390e3389">104</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Ellinghaus, D. et al. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. Preprint at https://www.medrxiv.org/content/early/2020/06/02/2020.05.31.20114991 (2020)." href="/articles/s41392-021-00736-8#ref-CR105" id="ref-link-section-d5157390e3392">105</a></sup> The <i>SLC6A20</i> gene encodes a transporter, signaling threshold regulating transmembrane adaptor, which functionally interacts with ACE2.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Ellinghaus, D. et al. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. Preprint at https://www.medrxiv.org/content/early/2020/06/02/2020.05.31.20114991 (2020)." href="/articles/s41392-021-00736-8#ref-CR105" id="ref-link-section-d5157390e3399">105</a></sup> The <i>CXCR6</i> gene and the <i>CCR9</i> gene encoding chemokine receptors are implicated in T cell differentiation and recruitment.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Schurr, T. G. Host genetic factors and susceptibility to SARS-CoV-2 infection. Am. J. Hum. Biol. 32, e23497 (2020)." href="/articles/s41392-021-00736-8#ref-CR95" id="ref-link-section-d5157390e3410">95</a></sup> Rs11385942 in the <i>LZTFL1</i> gene associated with increased <i>SLC6A20</i> expression and reduced <i>CXCR6</i> expression is a risk variant and is common in Europeans, Africans, and South Asians, but almost absent in the East Asians.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Wang, F. et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov. 6, 83 (2020)." href="/articles/s41392-021-00736-8#ref-CR106" id="ref-link-section-d5157390e3423">106</a></sup></p><p>Another study suggests that a 49.4 kb haplotype in high linkage disequilibrium (LD) on 3p21.31 is the most highly correlated to severe COVID-19, and this core haplotype is thought to have entered the human population from the Neanderthals, an extinct hominin ~40,000 to 60,000 years ago.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Zeberg, H. & Pääbo, S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature 587, 610–612 (2020)." href="/articles/s41392-021-00736-8#ref-CR107" id="ref-link-section-d5157390e3429">107</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Nelson, R. Risk variant for severe COVID-19 inherited from Neanderthals. Am. J. Med. Genet. A 182, 2203–2204 (2020)." href="/articles/s41392-021-00736-8#ref-CR108" id="ref-link-section-d5157390e3432">108</a></sup> Neanderthal-derived core haplotype frequency varies significantly among populations that 63% of the Bengalese, ~30% of the South Asians, 8% of the Europeans, 4% of the Americans, a lower frequency of the East Asians, and almost none of the Africans carry this risk haplotype.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Kwok, A. J., Mentzer, A. & Knight, J. C. Host genetics and infectious disease: new tools, insights and translational opportunities. Nat. Rev. Genet. 22, 137–153 (2021)." href="/articles/s41392-021-00736-8#ref-CR109" id="ref-link-section-d5157390e3436">109</a></sup> This could explain that Briton-originated studies showed higher mortality in COVID-19 patients of Bangladeshi ethnicity (~2 times higher) and of South Asian descent.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Nelson, R. Risk variant for severe COVID-19 inherited from Neanderthals. Am. J. Med. Genet. A 182, 2203–2204 (2020)." href="/articles/s41392-021-00736-8#ref-CR108" id="ref-link-section-d5157390e3440">108</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Patel, P., Hiam, L., Sowemimo, A., Devakumar, D. & McKee, M. Ethnicity and covid-19. BMJ 369, m2282 (2020)." href="/articles/s41392-021-00736-8#ref-CR110" id="ref-link-section-d5157390e3443">110</a></sup> Correspondingly, mortality rates reported on 14 July 2020 in South Africa, Japan, South Korea, and China were substantially lower than the Western countries (in North America and West Europe).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 111" title="Sornette, D., Mearns, E., Schatz, M., Wu, K. & Darcet, D. Interpreting, analysing and modelling COVID-19 mortality data. Nonlinear Dyn. 101, 1751–1776 (2020)." href="/articles/s41392-021-00736-8#ref-CR111" id="ref-link-section-d5157390e3447">111</a></sup> However, black individuals were at higher risk compared with white people in England and the United States.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Williamson, E. J. et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 584, 430–436 (2020)." href="#ref-CR112" id="ref-link-section-d5157390e3451">112</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Rentsch, C. T. et al. Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: a nationwide cohort study. PLoS Med. 17, e1003379 (2020)." href="#ref-CR113" id="ref-link-section-d5157390e3451_1">113</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 114" title="Webb Hooper, M., Nápoles, A. M. & Pérez-Stable, E. J. COVID-19 and racial/ethnic disparities. JAMA 323, 2466–2467 (2020)." href="/articles/s41392-021-00736-8#ref-CR114" id="ref-link-section-d5157390e3454">114</a></sup> This paradoxical fact may be explained by the impacts of other genetic and environmental factors.</p><h3 class="c-article__sub-heading" id="Sec11">6p21.3 and HLA genotype</h3><p>The HLA system containing nearly 27,000 alleles in classes I, II, and III is an exceedingly polymorphic region.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Lorente, L. et al. HLA genetic polymorphisms and prognosis of patients with COVID-19. Med. Intens. 45, 96–103 (2021)." href="/articles/s41392-021-00736-8#ref-CR115" id="ref-link-section-d5157390e3466">115</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="La Porta, C. A. M. & Zapperi, S. Estimating the binding of SARS-CoV-2 peptides to HLA class I in human subpopulations using artificial neural networks. Cell Syst. 11, 412–417 (2020)." href="/articles/s41392-021-00736-8#ref-CR116" id="ref-link-section-d5157390e3469">116</a></sup> Genetic variations across the <i>HLA</i>-<i>A</i>, <i>HLA</i>-<i>B</i>, <i>HLA</i>-<i>C</i>, <i>HLA</i>-<i>DR</i>, <i>HLA</i>-<i>DP</i>, and <i>HLA</i>-<i>DQ</i> genes, which encode MHC molecules, might change the process of viral infection by differentially mediating antiviral immunity.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Kwok, A. J., Mentzer, A. & Knight, J. C. Host genetics and infectious disease: new tools, insights and translational opportunities. Nat. Rev. Genet. 22, 137–153 (2021)." href="/articles/s41392-021-00736-8#ref-CR109" id="ref-link-section-d5157390e3511">109</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Tomita, Y., Ikeda, T., Sato, R. & Sakagami, T. Association between HLA gene polymorphisms and mortality of COVID-19: an in silico analysis. Immun. Inflamm. Dis. 8, 684–694 (2020)." href="/articles/s41392-021-00736-8#ref-CR117" id="ref-link-section-d5157390e3514">117</a></sup> Several studies suggest that there may be specific risk and protective HLA alleles or haplotypes for COVID-19 incidence and mortality.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Sakuraba, A., Haider, H. & Sato, T. Population difference in allele frequency of HLA-C*05 and its correlation with COVID-19 mortality. Viruses 12, 1333 (2020)." href="/articles/s41392-021-00736-8#ref-CR9" id="ref-link-section-d5157390e3518">9</a></sup>.</p><p>HLA-A and HLA-C were reported to have the relatively greatest and least capacities for presenting SARS-CoV-2, respectively, and HLA-B preferentially involves susceptibility to COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Nguyen, A. et al. Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2. J. Virol. 94 e00510–20 (2020)." href="/articles/s41392-021-00736-8#ref-CR16" id="ref-link-section-d5157390e3525">16</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Yung, Y. L. et al. Association of HLA-B22 serotype with SARS-CoV-2 susceptibility in Hong Kong Chinese patients. HLA 97, 127–132 (2021)." href="/articles/s41392-021-00736-8#ref-CR118" id="ref-link-section-d5157390e3528">118</a></sup> HLA-A*25:01, HLA-A*25:02, HLA-B*46:01, HLA-C*01:02, and HLA-B22 serotype, including HLA-B*54:01, HLA-B*55:01, HLA-B*55:07, HLA-B*55:12, and HLA-B*56:01, are weak presenters, and thus individuals with these alleles may be COVID-19 susceptible.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Yung, Y. L. et al. Association of HLA-B22 serotype with SARS-CoV-2 susceptibility in Hong Kong Chinese patients. HLA 97, 127–132 (2021)." href="#ref-CR118" id="ref-link-section-d5157390e3532">118</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Barquera, R. et al. Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide. HLA 96, 277–298 (2020)." href="#ref-CR119" id="ref-link-section-d5157390e3532_1">119</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Mohammadpour, S., Torshizi Esfahani, A., Halaji, M., Lak, M. & Ranjbar, R. An updated review of the association of host genetic factors with susceptibility and resistance to COVID-19. J. Cell. Physiol. 236, 49–54 (2021)." href="/articles/s41392-021-00736-8#ref-CR120" id="ref-link-section-d5157390e3535">120</a></sup> HLA-A*02 subtypes such as HLA-A*02:02, HLA-A*02:03, HLA-A*02:05, HLA-A*02:06, HLA-A*02:09, HLA-A*02:11, HLA-A*02:12, HLA-A*02:22, HLA-A*02:24, HLA-A*02:35, and HLA-A*02:40, as well as HLA-A*24:02, HLA-B*15:03, HLA-B*52:01, HLA-C*12:02, and HLA-C*12:03, are strong presenters for SARS-CoV-2 epitopes and predicted to be protective.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 119" title="Barquera, R. et al. Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide. HLA 96, 277–298 (2020)." href="/articles/s41392-021-00736-8#ref-CR119" id="ref-link-section-d5157390e3539">119</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Debnath, M., Banerjee, M. & Berk, M. Genetic gateways to COVID-19 infection: implications for risk, severity, and outcomes. FASEB J. 34, 8787–8795 (2020)." href="/articles/s41392-021-00736-8#ref-CR121" id="ref-link-section-d5157390e3542">121</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 122" title="Kiyotani, K., Toyoshima, Y., Nemoto, K. & Nakamura, Y. Bioinformatic prediction of potential T cell epitopes for SARS-CoV-2. J. Hum. Genet. 65, 569–575 (2020)." href="/articles/s41392-021-00736-8#ref-CR122" id="ref-link-section-d5157390e3545">122</a></sup> SARS-CoV-2 peptides presented by HLA-B*15:03 are common among human coronaviruses and enable cross-protective T cell-based immunity.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Mohammadpour, S., Torshizi Esfahani, A., Halaji, M., Lak, M. & Ranjbar, R. An updated review of the association of host genetic factors with susceptibility and resistance to COVID-19. J. Cell. Physiol. 236, 49–54 (2021)." href="/articles/s41392-021-00736-8#ref-CR120" id="ref-link-section-d5157390e3549">120</a></sup> HLA-A*02:01 has varying capacities for presenting SARS-CoV-2 antigens in different studies.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Zhao, J. et al. Relationship between the ABO blood group and the coronavirus disease 2019 (COVID-19) susceptibility. Clin. Infect. Dis. 73, 328–331 (2021)." href="/articles/s41392-021-00736-8#ref-CR15" id="ref-link-section-d5157390e3553">15</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Tomita, Y., Ikeda, T., Sato, R. & Sakagami, T. Association between HLA gene polymorphisms and mortality of COVID-19: an in silico analysis. Immun. Inflamm. Dis. 8, 684–694 (2020)." href="/articles/s41392-021-00736-8#ref-CR117" id="ref-link-section-d5157390e3556">117</a></sup></p><p>Several studies concluded that HLA-A*25, HLA-B*08, HLA-B*15:01, HLA-B*15:27, HLA-B*27:07, HLA-B*44, HLA-B*51, HLA-C*01, HLA-C*03, HLA-C*04:01, HLA-DRB1*15:01, HLA-DQA1_509, HLA-DQB1*04, and HLA-DQB1*06:02 were associated with higher occurrence and mortality, while HLA-B*14, HLA-B*18, and HLA-B*49 showed an inverse log-linear relationship with COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Littera, R. et al. Human leukocyte antigen complex and other immunogenetic and clinical factors influence susceptibility or protection to SARS-CoV-2 infection and severity of the disease course. The Sardinian experience. Front. Immunol. 11, 605688 (2020)." href="#ref-CR123" id="ref-link-section-d5157390e3562">123</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kolin, D. A., Kulm, S., Christos, P. J. & Elemento, O. Clinical, regional, and genetic characteristics of Covid-19 patients from UK Biobank. PLoS One 15, e0241264 (2020)." href="#ref-CR124" id="ref-link-section-d5157390e3562_1">124</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wang, W., Zhang, W., Zhang, J., He, J. & Zhu, F. Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19). HLA 96, 194–196 (2020)." href="#ref-CR125" id="ref-link-section-d5157390e3562_2">125</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Novelli, A. et al. HLA allele frequencies and susceptibility to COVID-19 in a group of 99 Italian patients. HLA 96, 610–614 (2020)." href="#ref-CR126" id="ref-link-section-d5157390e3562_3">126</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="Correale, P. et al. HLA-B*44 and C*01 prevalence correlates with COVID-19 spreading across Italy. Int. J. Mol. Sci. 21, 5205 (2020)." href="/articles/s41392-021-00736-8#ref-CR127" id="ref-link-section-d5157390e3565">127</a></sup> HLA-A*11 was positively associated with COVID-19 mortality, but another analysis suggested that HLA-A*11:01 could generate efficient antiviral responses.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Lorente, L. et al. HLA genetic polymorphisms and prognosis of patients with COVID-19. Med. Intens. 45, 96–103 (2021)." href="/articles/s41392-021-00736-8#ref-CR115" id="ref-link-section-d5157390e3569">115</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Tomita, Y., Ikeda, T., Sato, R. & Sakagami, T. Association between HLA gene polymorphisms and mortality of COVID-19: an in silico analysis. Immun. Inflamm. Dis. 8, 684–694 (2020)." href="/articles/s41392-021-00736-8#ref-CR117" id="ref-link-section-d5157390e3572">117</a></sup> HLA-DRB1*01:01 (severe 2.2% vs mild 0.5%), HLA-DRB1*14:04 (severe 2.0% vs mild 0.5%), and HLA-DQA1*01:01 (severe 2.9% vs mild 0.9%) are risk alleles for severe COVID-19, while HLA-DRB1*12:01 (severe 2.2% vs mild 3.7%) and HLA-DPB1*03:01 (severe 0.7% vs mild 4.5%) were protective.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Wang, F. et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov. 6, 83 (2020)." href="/articles/s41392-021-00736-8#ref-CR106" id="ref-link-section-d5157390e3576">106</a></sup> HLA-C*05 is significantly correlated to increased COVID-19 death risk and each increase of 1% in HLA-C*05 frequency is followed by an increase of 44 deaths/million. Its receptor KIR2DS4fl is located on natural killer (NK) cells and recognizes viral peptides bound to HLA-C*05 to generate a potent activation signal, leading to NK cell-induced hyperactive antiviral immunity jointly with HLA-C*05.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Sakuraba, A., Haider, H. & Sato, T. Population difference in allele frequency of HLA-C*05 and its correlation with COVID-19 mortality. Viruses 12, 1333 (2020)." href="/articles/s41392-021-00736-8#ref-CR9" id="ref-link-section-d5157390e3580">9</a></sup> Several South-East Asian and Oceania regions seem to correspond to higher predicted protective allele frequencies than other global regions based on data from the Allele Frequency Net Database (<a href="http://www.allelefrequencies.net/hla.asp">http://www.allelefrequencies.net/hla.asp</a>; Supplementary Fig. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41392-021-00736-8#MOESM1">S1</a>, <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41392-021-00736-8#MOESM1">2</a>). HLA-A*24:02 was found to bind the peptide VYIGDPAQL, which is a virus helicase fragment shared between SARS-CoV-2 and two common cold coronaviruses, human coronavirus OC43 and HKU1. Thus, it was assumed that the anti-VYIGDPAQL T cells primed by previous OC43 or HKU1 infections could be restimulated after SARS-CoV-2 infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 128" title="Dijkstra, J., Frenette, A. & Dixon, B. Most Japanese individuals are genetically predisposed to recognize an immunogenic protein fragment shared between COVID-19 and common cold coronaviruses. F1000Res. 10, 196 (2021)." href="/articles/s41392-021-00736-8#ref-CR128" id="ref-link-section-d5157390e3598">128</a></sup> HLA-A*24:02 allele carried by 25.5–98.0% of Chinese may partly explain the better epidemic prevention effect in China.</p><p>HLA is codominant and expresses all the alleles in the high gene density, complex LD, and homology regions.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Kwok, A. J., Mentzer, A. & Knight, J. C. Host genetics and infectious disease: new tools, insights and translational opportunities. Nat. Rev. Genet. 22, 137–153 (2021)." href="/articles/s41392-021-00736-8#ref-CR109" id="ref-link-section-d5157390e3605">109</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="La Porta, C. A. M. & Zapperi, S. Estimating the binding of SARS-CoV-2 peptides to HLA class I in human subpopulations using artificial neural networks. Cell Syst. 11, 412–417 (2020)." href="/articles/s41392-021-00736-8#ref-CR116" id="ref-link-section-d5157390e3608">116</a></sup> This suggests studying complete HLA genotypes for each individual rather than being limited to a few protective or harmful alleles as a wiser course.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 129" title="Iturrieta-Zuazo, I. et al. Possible role of HLA class-I genotype in SARS-CoV-2 infection and progression: a pilot study in a cohort of Covid-19 Spanish patients. Clin. Immunol. 219, 108572 (2020)." href="/articles/s41392-021-00736-8#ref-CR129" id="ref-link-section-d5157390e3612">129</a></sup> Haplotype HLA-A*11:01-B*51:01-C*14:02 was more common in severe COVID-19 patients than in mild ones.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Wang, F. et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov. 6, 83 (2020)." href="/articles/s41392-021-00736-8#ref-CR106" id="ref-link-section-d5157390e3616">106</a></sup> An Italian study found that haplotype HLA-A*01:01-B*08:01-C*07:01-DRB1*03:01 contributed to COVD-19 higher occurrence and mortality in northern Italy, while haplotype HLA-A*02:01-B*18:01-C*07:01-DRB1*11:04 closely linked to lower occurrence and mortality in central-southern Italy.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 130" title="Pisanti, S. et al. Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of COVID-19. J. Transl. Med. 18, 352 (2020)." href="/articles/s41392-021-00736-8#ref-CR130" id="ref-link-section-d5157390e3620">130</a></sup> A Sardinian study identified two haplotypes HLA-A*02:05-B*58:01-DRB1*08:01 and HLA-A*02:05-B*58:01-C*07:01 as being protective against severe COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 123" title="Littera, R. et al. Human leukocyte antigen complex and other immunogenetic and clinical factors influence susceptibility or protection to SARS-CoV-2 infection and severity of the disease course. The Sardinian experience. Front. Immunol. 11, 605688 (2020)." href="/articles/s41392-021-00736-8#ref-CR123" id="ref-link-section-d5157390e3624">123</a></sup></p><p>Since COVID-19 vaccines may have variable binding affinities with different HLA genotypes in different populations, predicting good binders across certain HLA alleles may contribute to design an efficacious COVID-19 vaccine with corresponding epitope targets.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 131" title="Prachar, M. et al. Identification and validation of 174 COVID-19 vaccine candidate epitopes reveals low performance of common epitope prediction tools. Sci. Rep. 10, 20465 (2020)." href="/articles/s41392-021-00736-8#ref-CR131" id="ref-link-section-d5157390e3631">131</a></sup></p><h3 class="c-article__sub-heading" id="Sec12">9q34.2 and the ABO, alpha 1–3-<i>N</i>-acetylgalactosaminyltransferase and alpha 1–3-galactosyltransferase gene (<i>ABO</i>)</h3><p>A, B, and O blood groups possess A-antigen, B-antigen, and the biosynthetic precursor H-antigen, respectively.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 132" title="Liu, N. et al. The impact of ABO blood group on COVID-19 infection risk and mortality: a systematic review and meta-analysis. Blood Rev. 48, 100785 (2020)." href="/articles/s41392-021-00736-8#ref-CR132" id="ref-link-section-d5157390e3649">132</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 133" title="Fan, Q. et al. Association between ABO blood group system and COVID-19 susceptibility in Wuhan. Front. Cell. Infect. Microbiol. 10, 404 (2020)." href="/articles/s41392-021-00736-8#ref-CR133" id="ref-link-section-d5157390e3652">133</a></sup> The antigen-encoding gene comprises A, B, and O alleles and is expressed in four genetic phenotypes.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 132" title="Liu, N. et al. The impact of ABO blood group on COVID-19 infection risk and mortality: a systematic review and meta-analysis. Blood Rev. 48, 100785 (2020)." href="/articles/s41392-021-00736-8#ref-CR132" id="ref-link-section-d5157390e3656">132</a></sup> SARS-CoV-2 susceptibility and survival following infection may relate to ABO blood groups. Individuals carrying blood group A have a higher COVID-19 risk, while blood group O exerts a relatively protective effect.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 132" title="Liu, N. et al. The impact of ABO blood group on COVID-19 infection risk and mortality: a systematic review and meta-analysis. Blood Rev. 48, 100785 (2020)." href="/articles/s41392-021-00736-8#ref-CR132" id="ref-link-section-d5157390e3660">132</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 134" title="Valenti, L. et al. Association of ABO blood group and secretor phenotype with severe COVID-19. Transfusion 60, 3067–3070 (2020)." href="/articles/s41392-021-00736-8#ref-CR134" id="ref-link-section-d5157390e3663">134</a></sup> In the blood group A, A-antigen causes more P-selectin and intercellular cell adhesion molecule 1 attached to endothelial cells to increase cardiovascular disease likelihood. Blood group O individuals with ~25% decreased levels of von Willebrand factor might have lower thrombotic disease risk.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Valenti, L. et al. Association of ABO blood group and secretor phenotype with severe COVID-19. Transfusion 60, 3067–3070 (2020)." href="#ref-CR134" id="ref-link-section-d5157390e3667">134</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Dai, X. ABO blood group predisposes to COVID-19 severity and cardiovascular diseases. Eur. J. Prev. Cardiol. 27, 1436–1437 (2020)." href="#ref-CR135" id="ref-link-section-d5157390e3667_1">135</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 136" title="Franchini, M., Crestani, S., Frattini, F., Sissa, C. & Bonfanti, C. ABO blood group and von Willebrand factor: biological implications. Clin. Chem. Lab. Med. 52, 1273–1276 (2014)." href="/articles/s41392-021-00736-8#ref-CR136" id="ref-link-section-d5157390e3670">136</a></sup> In the blood group B, natural anti-A antibodies might exert a neutralizing activity blocking adhesion between S proteins and ACE2.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 133" title="Fan, Q. et al. Association between ABO blood group system and COVID-19 susceptibility in Wuhan. Front. Cell. Infect. Microbiol. 10, 404 (2020)." href="/articles/s41392-021-00736-8#ref-CR133" id="ref-link-section-d5157390e3674">133</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 134" title="Valenti, L. et al. Association of ABO blood group and secretor phenotype with severe COVID-19. Transfusion 60, 3067–3070 (2020)." href="/articles/s41392-021-00736-8#ref-CR134" id="ref-link-section-d5157390e3677">134</a></sup></p><p>The GATC haplotype rs8176746–rs8176740–rs495828–rs12683493, of which position is coincident with <i>ABO</i> locus, is common in people with non-O blood groups and positively correlated to ACE activity, while blood group O is characterized by intermediate ACE activity.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 135" title="Dai, X. ABO blood group predisposes to COVID-19 severity and cardiovascular diseases. Eur. J. Prev. Cardiol. 27, 1436–1437 (2020)." href="/articles/s41392-021-00736-8#ref-CR135" id="ref-link-section-d5157390e3686">135</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 137" title="Terao, C. et al. Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus. Ann. Hum. Genet. 77, 465–471 (2013)." href="/articles/s41392-021-00736-8#ref-CR137" id="ref-link-section-d5157390e3689">137</a></sup> Variants account for 15% of ACE activity variance, of which rs8176746 and rs495828 may independently reckon 2.8% and 4.9%, respectively.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Terao, C. et al. Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus. Ann. Hum. Genet. 77, 465–471 (2013)." href="#ref-CR137" id="ref-link-section-d5157390e3693">137</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Chung, C. M. et al. A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor. Pharmacogenomics J. 10, 537–544 (2010)." href="#ref-CR138" id="ref-link-section-d5157390e3693_1">138</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 139" title="Yamagata University Genomic Cohort Consortium (YUGCC) Pleiotropic effect of common variants at ABO Glycosyltranferase locus in 9q32 on plasma levels of pancreatic lipase and angiotensin converting enzyme. PLoS One 9, e55903 (2014)." href="/articles/s41392-021-00736-8#ref-CR139" id="ref-link-section-d5157390e3696">139</a></sup> The <i>ABO</i> variant rs657152 was considered as a significant signal associating with severe COVID-19 in Italian and Spanish cohorts.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Ellinghaus, D. et al. Genomewide association study of severe COVID-19 with respiratory failure. N. Engl. J. Med. 383, 1522–1534 (2020)." href="/articles/s41392-021-00736-8#ref-CR104" id="ref-link-section-d5157390e3703">104</a></sup></p><h3 class="c-article__sub-heading" id="Sec13">9q34.3 and the dipeptidyl peptidase 7 gene (<i>DPP7</i>)</h3><p>A 1-base pair (bp) insertion in the <i>DPP7</i> gene destroying <i>DPP7</i> transcription may have a potential monogenic effect for asymptomatic COVID-19 in a Chinese family analysis.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Wang, F. et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov. 6, 83 (2020)." href="/articles/s41392-021-00736-8#ref-CR106" id="ref-link-section-d5157390e3725">106</a></sup> DPP7 known as a survival factor to maintain lymphocytes quiescently may potentially involve in COVID-19 immunopathogenesis.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 140" title="Mele, D. A., Bista, P., Baez, D. V. & Huber, B. T. Dipeptidyl peptidase 2 is an essential survival factor in the regulation of cell quiescence. Cell Cycle 8, 2425–2434 (2009)." href="/articles/s41392-021-00736-8#ref-CR140" id="ref-link-section-d5157390e3729">140</a></sup> The specific functional effects of the <i>DPP7</i> gene in COVID-19 still need further clarification.</p><h3 class="c-article__sub-heading" id="Sec14">11p15.5 and the interferon induced transmembrane protein 3 gene (<i>IFITM3</i>)</h3><p>The rs12252 C-allele homozygosity in the <i>IFITM3</i> gene relates to COVID-19 patient disease severity, and CC-homozygote patients have a 6.37 times higher risk of severity after a SARS-CoV-2 infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Pati, A., Padhi, S., Suvankar, S. & Panda, A. K. Minor allele of interferon-induced transmembrane protein 3 polymorphism (rs12252) is covered against severe acute respiratory syndrome coronavirus 2 infection and mortality: a worldwide epidemiological investigation. J. Infect. Dis. 223, 175–178 (2021)." href="#ref-CR141" id="ref-link-section-d5157390e3751">141</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Zhang, Y. et al. Interferon-induced transmembrane protein 3 genetic variant rs12252-C associated with disease severity in coronavirus disease 2019. J. Infect. Dis. 222, 34–37 (2020)." href="#ref-CR142" id="ref-link-section-d5157390e3751_1">142</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 143" title="Thevarajan, I. et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat. Med. 26, 453–455 (2020)." href="/articles/s41392-021-00736-8#ref-CR143" id="ref-link-section-d5157390e3754">143</a></sup> This association is not thought to stem directly from rs12252, but from a functional variant existing LD with rs12252 of <i>IFITM3</i> or a nearby gene.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 144" title="Gómez, J. et al. The interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19. Cytokine 137, 155354 (2021)." href="/articles/s41392-021-00736-8#ref-CR144" id="ref-link-section-d5157390e3761">144</a></sup> Rs34481144 A-allele (38–56% in Europeans, 2–14% in Africans, and 1–2% in Chinese) might increase COVID-19 susceptibility by triggering methylation of the <i>IFITM3</i> promoter to decrease <i>IFITM3</i> mRNA expression in CD8<sup>+</sup> T cells and depressing surrounding gene transcription.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 145" title="Nikoloudis, D., Kountouras, D. & Hiona, A. The frequency of combined IFITM3 haplotype involving the reference alleles of both rs12252 and rs34481144 is in line with COVID-19 standardized mortality ratio of ethnic groups in England. PeerJ 8, e10402 (2020)." href="/articles/s41392-021-00736-8#ref-CR145" id="ref-link-section-d5157390e3774">145</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 146" title="Allen, E. K. et al. SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. Nat. Med. 23, 975–983 (2017)." href="/articles/s41392-021-00736-8#ref-CR146" id="ref-link-section-d5157390e3777">146</a></sup></p><h3 class="c-article__sub-heading" id="Sec15">12q24.33 and the golgin A3 gene (<i>GOLGA3</i>)</h3><p>Pedigree analysis of Chinese suggested the splice acceptor variant rs143359233 in the <i>GOLGA3</i> gene potentially implicated in critically ill COVID-19 patients as a monogenic factor.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Wang, F. et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. Cell Discov. 6, 83 (2020)." href="/articles/s41392-021-00736-8#ref-CR106" id="ref-link-section-d5157390e3795">106</a></sup> The <i>GOLGA3</i> gene encodes a Golgi complex-associated protein, which participates in protein transportation, cell apoptosis, Golgi positioning, and spermatogenesis.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 147" title="Bentson, L. F. et al. New point mutation in Golga3 causes multiple defects in spermatogenesis. Andrology 1, 440–450 (2013)." href="/articles/s41392-021-00736-8#ref-CR147" id="ref-link-section-d5157390e3802">147</a></sup> Its defect was proved to lead to male infertility previously, but the reliable relationship between the <i>GOLGA3</i> gene and COVID-19 remains uncertain.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 147" title="Bentson, L. F. et al. New point mutation in Golga3 causes multiple defects in spermatogenesis. Andrology 1, 440–450 (2013)." href="/articles/s41392-021-00736-8#ref-CR147" id="ref-link-section-d5157390e3810">147</a></sup> <i>GOLGA3</i> may implicate COVID-19 severity by influencing the interaction of SARS-CoV-2 to innate immune pathways.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 148" title="Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020)." href="/articles/s41392-021-00736-8#ref-CR148" id="ref-link-section-d5157390e3817">148</a></sup></p><h3 class="c-article__sub-heading" id="Sec16">13q12.3 and the high mobility group box 1 gene (<i>HMGB1</i>)</h3><p>The <i>HMGB1</i> gene encodes a DNA-binding protein, which is a critical damage-associated molecular pattern (DAMP) and probably regulates a proviral gene expression program. HMGB1 may interact with Toll-like receptor 4 (TLR4) and the advanced glycosylation end-product specific receptor to induce cytokine storm in immune cells and <i>ACE2</i> expression in alveolar epithelial cells, further increasing COVID-19 susceptibility.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 149" title="Wei, J. et al. Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection. Cell 184, 76–91.e13 (2021)." href="/articles/s41392-021-00736-8#ref-CR149" id="ref-link-section-d5157390e3838">149</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 150" title="Chen, R. et al. HMGB1 as a potential biomarker and therapeutic target for severe COVID-19. Heliyon 6, e05672 (2020)." href="/articles/s41392-021-00736-8#ref-CR150" id="ref-link-section-d5157390e3841">150</a></sup></p><h3 class="c-article__sub-heading" id="Sec17">15q26.1 and the <i>FURIN</i> gene</h3><p>The <i>FURIN</i> gene encodes a ubiquitous membrane-bound pro-protein convertase that cleaves the SARS-CoV-2 S protein into the S1 and S2 subunits. Two highly frequent <i>FURIN</i> variants relating to upregulated FURIN in Africans, rs6226 (93%) and rs8039305 (81%), are associated with increased hypertension risk and SARS-CoV-2 infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 151" title="Al-Mulla, F. et al. ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: a time to implement precision medicine against COVID-19. Heliyon 7, e06133 (2021)." href="/articles/s41392-021-00736-8#ref-CR151" id="ref-link-section-d5157390e3862">151</a></sup> A common variant, rs4702, may directly reduce SARS-CoV-2 infection. The variant rs769208985 (p.Arg298Gln), representing glutamine residue by replacing arginine in a highly conserved position (R298), might influence FURIN recognition of the SARS-CoV-2 S protein.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Dobrindt, K. et al. Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection. Stem Cell Rep. 16, 505–518 (2021)." href="/articles/s41392-021-00736-8#ref-CR20" id="ref-link-section-d5157390e3866">20</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Latini, A. et al. COVID-19 and genetic variants of protein involved in the SARS-CoV-2 entry into the host cells. Genes 11, 1010 (2020)." href="/articles/s41392-021-00736-8#ref-CR70" id="ref-link-section-d5157390e3869">70</a></sup></p><h3 class="c-article__sub-heading" id="Sec18">17q23.3 and the <i>ACE</i> gene</h3><p>The insertion of an Alu repeat element into <i>ACE</i> intron 16 may result in alternative splicing in which the <i>ACE</i> I-allele leads to protein shortening and the loss of a catalytically active protein domain, while the <i>ACE</i> D-allele still maintains two active protein domains catalyzing Ang I to Ang II.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 152" title="Gemmati, D. & Tisato, V. Genetic hypothesis and pharmacogenetics side of renin-angiotensin-system in COVID-19. Genes 11, 1044 (2020)." href="/articles/s41392-021-00736-8#ref-CR152" id="ref-link-section-d5157390e3893">152</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 153" title="Purwaningroom, D. L., Saifurrohman, M., Widodo, Putri, J. F. & Lukitasari, M. Alteration of splicing pattern on angiotensin-converting enzyme gene due to the insertion of Alu elements. IJCB 4, 53–58 (2015)." href="/articles/s41392-021-00736-8#ref-CR153" id="ref-link-section-d5157390e3896">153</a></sup> Approximately 60% of ACE level variability in general populations is likely to be determined by the <i>ACE</i> I/D variant.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 154" title="Gemmati, D. et al. COVID-19 and individual genetic susceptibility/receptivity: role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-chromosome in males? Int. J. Mol. Sci. 21, 3474 (2020)." href="/articles/s41392-021-00736-8#ref-CR154" id="ref-link-section-d5157390e3904">154</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 155" title="Zheng, H. & Cao, J. J. Angiotensin-converting enzyme gene polymorphism and severe lung injury in patients with coronavirus disease 2019. Am. J. Pathol. 190, 2013–2017 (2020)." href="/articles/s41392-021-00736-8#ref-CR155" id="ref-link-section-d5157390e3907">155</a></sup> The I/D variant is associated with ACE circulating and tissue concentrations, which means that ACE activity levels in I/I carriers are about half of that of D/D carriers.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Arnold, R. H. COVID-19-does this disease kill due to imbalance of the renin angiotensin system (RAS) caused by genetic and gender differences in the response to viral ACE2 attack? Heart Lung Circ. 29, 964–972 (2020)." href="/articles/s41392-021-00736-8#ref-CR87" id="ref-link-section-d5157390e3911">87</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 156" title="Delanghe, J. R., Speeckaert, M. M. & De Buyzere, M. L. COVID-19 infections are also affected by human ACE1 D/I polymorphism. Clin. Chem. Lab. Med. 58, 1125–1126 (2020)." href="/articles/s41392-021-00736-8#ref-CR156" id="ref-link-section-d5157390e3914">156</a></sup> COVID-19 variable recovery and prevalence rates correlate to the ratio of the <i>ACE</i> I/D allele frequency and the geographical variations of the <i>ACE</i> I/D variant.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 157" title="Delanghe, J. R., Speeckaert, M. M. & De Buyzere, M. L. The host’s angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections. Clin. Chim. Acta 505, 192–193 (2020)." href="/articles/s41392-021-00736-8#ref-CR157" id="ref-link-section-d5157390e3924">157</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 158" title="Hatami, N. et al. Worldwide ACE (I/D) polymorphism may affect COVID-19 recovery rate: an ecological meta-regression. Endocrine 68, 479–484 (2020)." href="/articles/s41392-021-00736-8#ref-CR158" id="ref-link-section-d5157390e3927">158</a></sup></p><p>The racial difference in the <i>ACE</i> gene polymorphism is well understood. According to the “thrifty genotype” hypothesis put forward by J.V. Neel, after modern human ancestors expanded out of Africa ~200,000 years ago, genetic variation of the D-allele occurred as the D-allele favoring the retention of salt and water became detrimental.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 159" title="Li, X., Sun, X., Jin, L. & Xue, F. Worldwide spatial genetic structure of angiotensin-converting enzyme gene: a new evolutionary ecological evidence for the thrifty genotype hypothesis. Eur. J. Hum. Genet. 19, 1002–1008 (2011)." href="/articles/s41392-021-00736-8#ref-CR159" id="ref-link-section-d5157390e3936">159</a></sup> Middle Eastern populations, particularly those in Lebanon with a relatively low I-allele frequency, are believed to be the ancestor of the <i>ACE</i> variant.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 86" title="Yamamoto, N. et al. SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype. Gene 758, 144944 (2020)." href="/articles/s41392-021-00736-8#ref-CR86" id="ref-link-section-d5157390e3943">86</a></sup> I/I genotype increases westwards and eastwards from the Middle East. The distribution of D-allele is characterized by the highest frequency of D-allele in Africa and Arab regions, medium frequencies in Europe, Australia, and America, and the lowest frequency in East Asia.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 159" title="Li, X., Sun, X., Jin, L. & Xue, F. Worldwide spatial genetic structure of angiotensin-converting enzyme gene: a new evolutionary ecological evidence for the thrifty genotype hypothesis. Eur. J. Hum. Genet. 19, 1002–1008 (2011)." href="/articles/s41392-021-00736-8#ref-CR159" id="ref-link-section-d5157390e3947">159</a></sup> Therefore, the higher recovery rate in East Asians and disproportionately higher fatality rate in African Americans are unsurprising.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 155" title="Zheng, H. & Cao, J. J. Angiotensin-converting enzyme gene polymorphism and severe lung injury in patients with coronavirus disease 2019. Am. J. Pathol. 190, 2013–2017 (2020)." href="/articles/s41392-021-00736-8#ref-CR155" id="ref-link-section-d5157390e3952">155</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 158" title="Hatami, N. et al. Worldwide ACE (I/D) polymorphism may affect COVID-19 recovery rate: an ecological meta-regression. Endocrine 68, 479–484 (2020)." href="/articles/s41392-021-00736-8#ref-CR158" id="ref-link-section-d5157390e3955">158</a></sup></p><h3 class="c-article__sub-heading" id="Sec19">19q13.32 and the apolipoprotein E gene (<i>APOE</i>)</h3><p>The <i>APOE</i> gene has three common alleles, ε2, ε3, and ε4, which are haplotypes of rs429358 and rs7412.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 160" title="Anastassopoulou, C., Gkizarioti, Z., Patrinos, G. P. & Tsakris, A. Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity. Hum. Genomics 14, 40 (2020)." href="/articles/s41392-021-00736-8#ref-CR160" id="ref-link-section-d5157390e3974">160</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 161" title="Kasparian, K., Graykowski, D. & Cudaback, E. Commentary: APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort. Front. Immunol. 11, 1939 (2020)." href="/articles/s41392-021-00736-8#ref-CR161" id="ref-link-section-d5157390e3977">161</a></sup> Compared to the most common <i>APOE</i> ε3ε3 genotype, individuals who are homozygous for <i>APOE</i> ε4 have twice the risk of severe COVID-19, although mortalities between <i>APOE</i> ε3ε4 and ε3ε3 COVID-19-positive subjects have no significant difference.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 162" title="Inal, J. Biological factors linking APOE ε4 variant and severe COVID-19. Curr. Atheroscler. Rep. 22, 70 (2020)." href="/articles/s41392-021-00736-8#ref-CR162" id="ref-link-section-d5157390e3991">162</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 163" title="Kuo, C. L. et al. APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort. J. Gerontol. A Biol. Sci. Med. Sci. 75, 2231–2232 (2020)." href="/articles/s41392-021-00736-8#ref-CR163" id="ref-link-section-d5157390e3994">163</a></sup> The <i>APOE</i> ε4ε4 homozygous genotype might have a higher risk of severe COVID-19 due to regulating proinflammatory pathways and lipoprotein function being affected.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 161" title="Kasparian, K., Graykowski, D. & Cudaback, E. Commentary: APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort. Front. Immunol. 11, 1939 (2020)." href="/articles/s41392-021-00736-8#ref-CR161" id="ref-link-section-d5157390e4001">161</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 163" title="Kuo, C. L. et al. APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort. J. Gerontol. A Biol. Sci. Med. Sci. 75, 2231–2232 (2020)." href="/articles/s41392-021-00736-8#ref-CR163" id="ref-link-section-d5157390e4004">163</a></sup> An African-American ε4-allele frequency of 29.5% compared to a Caucasian rate of 12.1% may explain the diverse mortalities.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 162" title="Inal, J. Biological factors linking APOE ε4 variant and severe COVID-19. Curr. Atheroscler. Rep. 22, 70 (2020)." href="/articles/s41392-021-00736-8#ref-CR162" id="ref-link-section-d5157390e4008">162</a></sup></p><h3 class="c-article__sub-heading" id="Sec20">21q22.3 and the <i>TMPRSS2</i> gene</h3><p>The <i>TMPRSS2</i> gene variants may play a significant role in the interindividual differences particularly in the gender-related bias of COVID-19 susceptibility and severity.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 164" title="Alshahawey, M., Raslan, M. & Sabri, N. Sex-mediated effects of ACE2 and TMPRSS2 on the incidence and severity of COVID-19; the need for genetic implementation. Curr. Res. Transl. Med. 68, 149–150 (2020)." href="/articles/s41392-021-00736-8#ref-CR164" id="ref-link-section-d5157390e4026">164</a></sup> Rs61299115, rs4303794, and rs11088551 have relatively high frequencies in the general populations (25–36%), but much lower, 2%, in East Asian populations. They potentially enhance <i>TMPRSS2</i> transcription, and thus the rarity of these three single-nucleotide variants (SNVs) among the East Asians results in lower <i>TMPRSS2</i> expression levels.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 165" title="Barash, A., Machluf, Y., Ariel, I. & Dekel, Y. The pursuit of COVID-19 biomarkers: putting the spotlight on ACE2 and TMPRSS2 regulatory sequences. Front. Med. 7, 582793 (2020)." href="/articles/s41392-021-00736-8#ref-CR165" id="ref-link-section-d5157390e4036">165</a></sup> Rs12329760 (p.Val197Met) located at the exonic splicing enhancer site might considerably increase the <i>TMPRSS2</i> faulty expression, weaken TMPRSS2 stability, and inhibit S protein and ACE2 interaction, which may contribute to asymptomatic and mild patients in Chinese with higher variant frequency.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 166" title="Singh, H., Choudhari, R., Nema, V. & Khan, A. A. ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease. Microb. Pathogenesis 150, 104621 (2021)." href="/articles/s41392-021-00736-8#ref-CR166" id="ref-link-section-d5157390e4044">166</a></sup> However, in Italian populations, rs12329760, as well as a haplotype rs2070788–rs9974589–rs7364083–rs8134378, trigger increased <i>TMPRSS2</i> expression and may explain the higher mortality rate among the Italians with higher variant frequency.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 167" title="Yildirim, Z., Sahin, O. S., Yazar, S. & Bozok Cetintas, V. Genetic and epigenetic factors associated with increased severity of Covid-19. Cell Biol. Int. 45, 1158–1174 (2021)." href="/articles/s41392-021-00736-8#ref-CR167" id="ref-link-section-d5157390e4051">167</a></sup> Rs8134378 close to an androgen-responsive enhancer possibly increases the <i>TMPRSS2</i> gene expression in males in an androgen-specific manner and is co-regulated with a “European” haplotype rs463727–rs34624090–rs55964536–rs734056–rs4290734–rs34783969–rs11702475–rs35899679–rs35041537.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 168" title="Choudhary, S., Sreenivasulu, K., Mitra, P., Misra, S. & Sharma, P. Role of genetic variants and gene expression in the susceptibility and severity of COVID-19. Ann. Lab. Med. 41, 129–138 (2021)." href="/articles/s41392-021-00736-8#ref-CR168" id="ref-link-section-d5157390e4058">168</a></sup> The variants rs2070788, rs464397, rs469390 (p.Val379Ile), and rs383510 could upregulate <i>TMPRSS2</i> expression in lung tissue and have lower frequencies in East Asians than Africans, Europeans, and Americans, which might explain the different COVID-19 susceptibilities in different populations.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 169" title="Irham, L. M. et al. Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents. Biochem. Biophys. Res. Commun. 529, 263–269 (2020)." href="/articles/s41392-021-00736-8#ref-CR169" id="ref-link-section-d5157390e4066">169</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 170" title="Piva, F., Sabanovic, B., Cecati, M. & Giulietti, M. Expression and co-expression analyses of TMPRSS2, a key element in COVID-19. Eur. J. Clin. Microbiol. Infect. Dis. 40, 451–455 (2021)." href="/articles/s41392-021-00736-8#ref-CR170" id="ref-link-section-d5157390e4069">170</a></sup> Conversely, p.Asp435Tyr only presenting at a low frequency in Europeans leads to the lack of a key residue catalyzing substrate binding.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 171" title="Hou, Y. et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med. 18, 216 (2020)." href="/articles/s41392-021-00736-8#ref-CR171" id="ref-link-section-d5157390e4073">171</a></sup></p></div></div></section><section data-title="X- or Y-linked loci and genes associated with COVID-19"><div class="c-article-section" id="Sec21-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec21">X- or Y-linked loci and genes associated with COVID-19</h2><div class="c-article-section__content" id="Sec21-content"><p>Consistent with Lyon’s theory, X-chromosome inactivation (XCI), which occurs in females in the late blastocyst stage, is a fundamental event in the epigenetic gene regulation that one of the X chromosomes is stochastically inactivated to equal X-linked gene dosage between genders.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 167" title="Yildirim, Z., Sahin, O. S., Yazar, S. & Bozok Cetintas, V. Genetic and epigenetic factors associated with increased severity of Covid-19. Cell Biol. Int. 45, 1158–1174 (2021)." href="/articles/s41392-021-00736-8#ref-CR167" id="ref-link-section-d5157390e4086">167</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Foresta, C. & Rocca, M. S. & Di Nisio, A. Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome. J. Endocrinol. Invest. 16, 1–6 (2020)." href="#ref-CR172" id="ref-link-section-d5157390e4089">172</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Kloc, M., Ghobrial, R. M. & Kubiak, J. Z. The role of genetic sex and mitochondria in response to COVID-19 infection. Int. Arch. Allergy Immunol. 181, 629–634 (2020)." href="#ref-CR173" id="ref-link-section-d5157390e4089_1">173</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 174" title="Li, Y., Jerkic, M., Slutsky, A. S. & Zhang, H. Molecular mechanisms of sex bias differences in COVID-19 mortality. Crit. Care 24, 405 (2020)." href="/articles/s41392-021-00736-8#ref-CR174" id="ref-link-section-d5157390e4092">174</a></sup> Two noncoding RNAs control this complex inactivation process, which condenses one X chromosome into a compact structure, Barr body, and maintains an active X chromosome simultaneously. Approximately 15–30% of X-linked genes, most are on the short arm (p), can escape from the XCI.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 172" title="Foresta, C. & Rocca, M. S. & Di Nisio, A. Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome. J. Endocrinol. Invest. 16, 1–6 (2020)." href="/articles/s41392-021-00736-8#ref-CR172" id="ref-link-section-d5157390e4096">172</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 175" title="Viveiros, A. et al. Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones. Am. J. Physiol. Heart Circ. Physiol. 320, H296–H304 (2021)." href="/articles/s41392-021-00736-8#ref-CR175" id="ref-link-section-d5157390e4099">175</a></sup> Interestingly, XCI is cell-specific such that some cells express the maternal copy, while others express the paternal copy, and escape from XCI can be variable between individuals, among cells in a tissue, and during growth and aging.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 176" title="Gadi, N., Wu, S. C., Spihlman, A. P. & Moulton, V. R. What’s sex got to do with COVID-19? Gender-based differences in the host immune response to coronaviruses. Front. Immunol. 11, 2147 (2020)." href="/articles/s41392-021-00736-8#ref-CR176" id="ref-link-section-d5157390e4103">176</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 177" title="Wang, J. et al. Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc. Natl. Acad. Sci. USA 113, E2029–E2038 (2016)." href="/articles/s41392-021-00736-8#ref-CR177" id="ref-link-section-d5157390e4106">177</a></sup> The skewed XCI may bypass the deleterious X-linked variants in females, while any abnormal gene variants on the X chromosome of males are more likely to express phenotypically and to cause more pronounced consequences due to hemizygosity.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 160" title="Anastassopoulou, C., Gkizarioti, Z., Patrinos, G. P. & Tsakris, A. Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity. Hum. Genomics 14, 40 (2020)." href="/articles/s41392-021-00736-8#ref-CR160" id="ref-link-section-d5157390e4110">160</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 175" title="Viveiros, A. et al. Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones. Am. J. Physiol. Heart Circ. Physiol. 320, H296–H304 (2021)." href="/articles/s41392-021-00736-8#ref-CR175" id="ref-link-section-d5157390e4113">175</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 178" title="Kelada, M., Anto, A., Dave, K. & Saleh, S. N. The role of sex in the risk of mortality from COVID-19 amongst adult patients: a systematic review. Cureus 12, e10114 (2020)." href="/articles/s41392-021-00736-8#ref-CR178" id="ref-link-section-d5157390e4116">178</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 179" title="Penna, C., Mercurio, V., Tocchetti, C. G. & Pagliaro, P. Sex-related differences in COVID-19 lethality. Br. J. Pharmacol. 177, 4375–4385 (2020)." href="/articles/s41392-021-00736-8#ref-CR179" id="ref-link-section-d5157390e4119">179</a></sup> This appears to explain SARS-CoV-2 infection rate gender bias.</p><h3 class="c-article__sub-heading" id="Sec22">Xp22.2 and the <i>TLR7</i> gene</h3><p>The <i>TLR7</i> gene encodes a Toll-like receptor that could recognize SARS-CoV-2 RNA and trigger the antiviral response.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 180" title="van de Veerdonk, F. L. & Netea, M. G. Rare variants increase the risk of severe COVID-19. Elife 10, e67860 (2021)." href="/articles/s41392-021-00736-8#ref-CR180" id="ref-link-section-d5157390e4137">180</a></sup> An analysis performed on two young brother pairs with severe COVID-19 identified a maternally inherited variant rs2042915990 (p.Gln710Argfs*18) and a missense variant rs200553089 (p.Val795Phe) as rare loss-of-function (LOF) variants in the <i>TLR7</i> gene, which result in immunodeficiencies in type I and II interferon responses.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 181" title="van der Made, C. I. et al. Presence of genetic variants among young men with severe COVID-19. JAMA 324, 663–673 (2020)." href="/articles/s41392-021-00736-8#ref-CR181" id="ref-link-section-d5157390e4144">181</a></sup> Further, a nested case–control study identified the <i>TLR7</i> gene variants p.Ser301Pro, rs189681811 (p.Arg920Lys), and rs147244662 (p.Ala1032Thr) as LOF variants, which in young, male, severe COVID-19 patients were considered to account for COVID-19 susceptibility in up to 2% cases.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 182" title="Fallerini, C. et al. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study. Elife 10, e67569 (2021)." href="/articles/s41392-021-00736-8#ref-CR182" id="ref-link-section-d5157390e4152">182</a></sup></p><h3 class="c-article__sub-heading" id="Sec23">Xp22.22 and the <i>ACE2</i> gene</h3><p>The <i>ACE2</i> gene encoding a dipeptidyl carboxydipeptidase with 805 amino acids is a putative risk factor for SARS-CoV-2 infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Verdecchia, P., Cavallini, C., Spanevello, A. & Angeli, F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur. J. Intern. Med. 76, 14–20 (2020)." href="/articles/s41392-021-00736-8#ref-CR72" id="ref-link-section-d5157390e4170">72</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 183" title="Ghafouri-Fard, S. et al. Effects of host genetic variations on response to, susceptibility and severity of respiratory infections. Biomed. Pharmacother. 128, 110296 (2020)." href="/articles/s41392-021-00736-8#ref-CR183" id="ref-link-section-d5157390e4173">183</a></sup> ACE2 contains a potential N-terminal signal peptide, a peptidase domain, and a C-terminal collectrin-like domain, which ends with the single transmembrane helix. A ferredoxin-like fold “Neck” domain is between the peptidase domain and transmembrane helix. The crucial roles of the peptidase and neck domains (residues 19–726) in the ACE2 homodimerization allow for positing that variants affecting these amino acid residues may influence viral infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Darbani, B. The expression and polymorphism of entry machinery for COVID-19 in human: juxtaposing population groups, gender, and different tissues. Int. J. Environ. Res. Public Health 17, 3433 (2020)." href="#ref-CR184" id="ref-link-section-d5157390e4177">184</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Devaux, C. A., Rolain, J. M. & Raoult, D. ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J. Microbiol. Immunol. Infect. 53, 425–435 (2020)." href="#ref-CR185" id="ref-link-section-d5157390e4177_1">185</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Tipnis, S. R. et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J. Biol. Chem. 275, 33238–33243 (2000)." href="#ref-CR186" id="ref-link-section-d5157390e4177_2">186</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 187" title="Yan, R. et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367, 1444–1448 (2020)." href="/articles/s41392-021-00736-8#ref-CR187" id="ref-link-section-d5157390e4180">187</a></sup></p><p>Up to the date of this writing, no genetically monogenic, naturally resistant <i>ACE2</i> mutations which counter S protein binding have been reported.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 188" title="Cao, Y. et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 6, 11 (2020)." href="/articles/s41392-021-00736-8#ref-CR188" id="ref-link-section-d5157390e4189">188</a></sup> However, a number of <i>ACE2</i> variants may influence COVID-19 susceptibility and outcomes via three primary routines: (1) alterations of ACE2-binding properties to sirtuin 1, which regulates transcriptional and post-translational modifications of the <i>ACE2</i> gene, (2) alteration of the soluble ACE2 levels in circulation and the affinity and density of ACE2 for the S protein, and (3) alteration of circulating Ang-(1–7), which causes a greater marked RAAS imbalance and greater disease severity.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 80" title="Sieńko, J. et al. COVID-19: the influence of ACE genotype and ACE-I and ARBs on the course of SARS-CoV-2 infection in elderly patients. Clin. Inter. Aging 15, 1231–1240 (2020)." href="/articles/s41392-021-00736-8#ref-CR80" id="ref-link-section-d5157390e4199">80</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Arnold, R. H. COVID-19-does this disease kill due to imbalance of the renin angiotensin system (RAS) caused by genetic and gender differences in the response to viral ACE2 attack? Heart Lung Circ. 29, 964–972 (2020)." href="/articles/s41392-021-00736-8#ref-CR87" id="ref-link-section-d5157390e4202">87</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 185" title="Devaux, C. A., Rolain, J. M. & Raoult, D. ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J. Microbiol. Immunol. Infect. 53, 425–435 (2020)." href="/articles/s41392-021-00736-8#ref-CR185" id="ref-link-section-d5157390e4205">185</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 189" title="Mariappan, V., Rao, S. R. & Balakrishna Pillai, A. Angiotensin-converting enzyme 2: a protective factor in regulating disease virulence of SARS-COV-2. IUBMB Life 72, 2533–2545 (2020)." href="/articles/s41392-021-00736-8#ref-CR189" id="ref-link-section-d5157390e4208">189</a></sup></p><p>Among the most significant variants for ACE2 activity and levels, the most frequent is the transition rs2285666 (G8790A).<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 152" title="Gemmati, D. & Tisato, V. Genetic hypothesis and pharmacogenetics side of renin-angiotensin-system in COVID-19. Genes 11, 1044 (2020)." href="/articles/s41392-021-00736-8#ref-CR152" id="ref-link-section-d5157390e4214">152</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 190" title="Iyer, G. R. et al. Infectivity and progression of COVID-19 based on selected host candidate gene variants. Front. Genet. 11, 861 (2020)." href="/articles/s41392-021-00736-8#ref-CR190" id="ref-link-section-d5157390e4217">190</a></sup> The A-allele carriers may have higher serum ACE2 levels than the G-allele carriers, of which A/A genotype had almost 50% higher <i>ACE2</i> expression levels than the G/G genotype.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 191" title="Wu, Y. H., Li, J. Y., Wang, C., Zhang, L. M. & Qiao, H. The ACE2 G8790A polymorphism: involvement in type 2 diabetes mellitus combined with cerebral stroke. J. Clin. Lab. Anal. 31, e22033 (2017)." href="/articles/s41392-021-00736-8#ref-CR191" id="ref-link-section-d5157390e4224">191</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 192" title="Asselta, R., Paraboschi, E. M., Mantovani, A. & Duga, S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging 12, 10087–10098 (2020)." href="/articles/s41392-021-00736-8#ref-CR192" id="ref-link-section-d5157390e4227">192</a></sup> Rs2285666 located in the intronic-consensus splice site region might theoretically affect the processing of total RNA to mRNA with alternative splicing mechanisms and further the amount of protein.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 193" title="Srivastava, A. et al. Genetic association of ACE2 rs2285666 polymorphism with COVID-19 spatial distribution in India. Front. Genet. 11, 564741 (2020)." href="/articles/s41392-021-00736-8#ref-CR193" id="ref-link-section-d5157390e4231">193</a></sup> The transition G8790A was predicted to lead to ~9.2% increased strength of the splice site and further elevated ACE2 serum levels.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 192" title="Asselta, R., Paraboschi, E. M., Mantovani, A. & Duga, S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging 12, 10087–10098 (2020)." href="/articles/s41392-021-00736-8#ref-CR192" id="ref-link-section-d5157390e4235">192</a></sup> Accordingly, rs2285666 is suggested to be a protective variant to COVID-19, and lower morbidity and mortality in Indians could be explained by the A-allele of rs2285666.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 193" title="Srivastava, A. et al. Genetic association of ACE2 rs2285666 polymorphism with COVID-19 spatial distribution in India. Front. Genet. 11, 564741 (2020)." href="/articles/s41392-021-00736-8#ref-CR193" id="ref-link-section-d5157390e4240">193</a></sup> The variant rs2106809 reported in Indians and Saudi Arabians may primarily influence serum ACE2 levels, and that the C/C or C/T genotype has comparatively higher levels than the T/T genotype.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 166" title="Singh, H., Choudhari, R., Nema, V. & Khan, A. A. ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease. Microb. Pathogenesis 150, 104621 (2021)." href="/articles/s41392-021-00736-8#ref-CR166" id="ref-link-section-d5157390e4244">166</a></sup></p><p>Rs4646114 and rs4646115, which are more prevalent in African descent populations with frequencies of 5.0–7.2% and 1.4–1.8%, could accelerate viral infection and spread, and thus may associate with higher COVID-19 susceptibility.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 165" title="Barash, A., Machluf, Y., Ariel, I. & Dekel, Y. The pursuit of COVID-19 biomarkers: putting the spotlight on ACE2 and TMPRSS2 regulatory sequences. Front. Med. 7, 582793 (2020)." href="/articles/s41392-021-00736-8#ref-CR165" id="ref-link-section-d5157390e4250">165</a></sup> Rs4646116 (p.Lys26Arg), which is quite frequent in Caucasians, but has not yet been detected in the East-Asian populations, activates ACE2 and boosts binding to S protein, while rs191860450 (p.Ile468Val), which is more prevalent in Asians, may alter the ACE2–S protein interaction characteristics, but the significance of this is unclear.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 183" title="Ghafouri-Fard, S. et al. Effects of host genetic variations on response to, susceptibility and severity of respiratory infections. Biomed. Pharmacother. 128, 110296 (2020)." href="/articles/s41392-021-00736-8#ref-CR183" id="ref-link-section-d5157390e4254">183</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 194" title="Li, Q., Cao, Z. & Rahman, P. Genetic variability of human angiotensin-converting enzyme 2 (hACE2) among various ethnic populations. Mol. Genet. Genom. Med. 8, e1344 (2020)." href="/articles/s41392-021-00736-8#ref-CR194" id="ref-link-section-d5157390e4257">194</a></sup> The variant p.Arg514Gly, located in the AGT–ACE2 interaction surface, was predicted to increase COVID-19 risk by altering RAAS function.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 171" title="Hou, Y. et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med. 18, 216 (2020)." href="/articles/s41392-021-00736-8#ref-CR171" id="ref-link-section-d5157390e4261">171</a></sup> The higher COVID-19 mortality in Italy may be partly explained by the role of rs41303171 (p.Asn720Asp), which is more prevalently carried by Italians, in promoting TMPRSS2 cleaving and viral intake.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 195" title="Lippi, G., Lavie, C. J., Henry, B. M. & Sanchis-Gomar, F. Do genetic polymorphisms in angiotensin converting enzyme 2 (ACE2) gene play a role in coronavirus disease 2019 (COVID-19)? Clin. Chem. Lab. Med. 58, 1415–1422 (2020)." href="/articles/s41392-021-00736-8#ref-CR195" id="ref-link-section-d5157390e4265">195</a></sup></p><p>The variants rs73635825 (p.Ser19Pro) and rs766996587 (p.Met82Ile) exclusively presented in Africans may reduce encoded protein stability and binding affinity to S protein binding sites.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Ravaioli, S. et al. ACE2 and TMPRSS2 potential involvement in genetic susceptibility to SARS-CoV-2 in cancer patients. Cell Transplant. 29, 963689720968749 (2020)." href="/articles/s41392-021-00736-8#ref-CR4" id="ref-link-section-d5157390e4272">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Calcagnile, M. et al. Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 spike protein. Biochimie 180, 143–148 (2021)." href="/articles/s41392-021-00736-8#ref-CR8" id="ref-link-section-d5157390e4275">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 196" title="Hussain, M. et al. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. J. Med. Virol. 92, 1580–1586 (2020)." href="/articles/s41392-021-00736-8#ref-CR196" id="ref-link-section-d5157390e4278">196</a></sup> The European-specific variant rs1448326240 (p.Glu239His) is thought to be an interaction-inhibiting variant and lead to a lower SARS-CoV-2 susceptibility.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 184" title="Darbani, B. The expression and polymorphism of entry machinery for COVID-19 in human: juxtaposing population groups, gender, and different tissues. Int. J. Environ. Res. Public Health 17, 3433 (2020)." href="/articles/s41392-021-00736-8#ref-CR184" id="ref-link-section-d5157390e4282">184</a></sup> Rs143936283 (p.Glu329Gly) has a lower binding affinity for the S protein, implying that rs143936283 may confer a lower probability of viral attachment and some level of resistance against infection.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 195" title="Lippi, G., Lavie, C. J., Henry, B. M. & Sanchis-Gomar, F. Do genetic polymorphisms in angiotensin converting enzyme 2 (ACE2) gene play a role in coronavirus disease 2019 (COVID-19)? Clin. Chem. Lab. Med. 58, 1415–1422 (2020)." href="/articles/s41392-021-00736-8#ref-CR195" id="ref-link-section-d5157390e4286">195</a></sup> The variants p.Leu351Val and rs762890235 (p.Pro389His), which occur in the ACE2–S protein interaction region, are predicted to interfere with the internalization process.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 197" title="Benetti, E. et al. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population. Eur. J. Hum. Genet. 28, 1602–1614 (2020)." href="/articles/s41392-021-00736-8#ref-CR197" id="ref-link-section-d5157390e4290">197</a></sup> Rs961360700 (p.Asp355Asn) and rs1396769231 (p.Met383Thr) were also predicted to adversely affect ACE2 stability.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 196" title="Hussain, M. et al. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. J. Med. Virol. 92, 1580–1586 (2020)." href="/articles/s41392-021-00736-8#ref-CR196" id="ref-link-section-d5157390e4294">196</a></sup> The four variants located in the ACE2 dimeric interface, p.Arg708Trp, p.Arg710Cys, p.Arg710His, and p.Arg716Cys, could affect ACE2 cleavage by TMPRSS2 and change the dimer formation, which may be responsible for the milder COVID-19 symptoms in Europeans having these four variants.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 171" title="Hou, Y. et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med. 18, 216 (2020)." href="/articles/s41392-021-00736-8#ref-CR171" id="ref-link-section-d5157390e4299">171</a></sup></p><p>Heterogeneous <i>ACE2</i> expression in different ethnic groups might be a measure of differential population reactions to COVID-19. For example, Asians have a higher <i>ACE2</i> expression than African Americans and Caucasians. The expression quantitative loci for upregulating <i>ACE2</i> can be up to almost 100% in East Asians, which are over 30% higher than other racial groups.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 185" title="Devaux, C. A., Rolain, J. M. & Raoult, D. ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J. Microbiol. Immunol. Infect. 53, 425–435 (2020)." href="/articles/s41392-021-00736-8#ref-CR185" id="ref-link-section-d5157390e4314">185</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 198" title="Chen, J. et al. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 19, e13168 (2020)." href="/articles/s41392-021-00736-8#ref-CR198" id="ref-link-section-d5157390e4317">198</a></sup> The prevalence of <i>ACE2</i>-downregulating variants is 54% in non-Finnish Europeans, 39% in Africans/African Americans, and 2–10% in Latinos/admixed Americans, East Asians, Finns, and South Asians, while Amish and Ashkenazi Jewish populations seem to carry none of such variants.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 171" title="Hou, Y. et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Med. 18, 216 (2020)." href="/articles/s41392-021-00736-8#ref-CR171" id="ref-link-section-d5157390e4325">171</a></sup> Highly penetrant dominant trait presenting in the <i>ACE2</i> gene probably affects familial clusters.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Ikitimur, H. et al. Determining host factors contributing to disease severity in a family cluster of 29 hospitalized SARS-CoV-2 patients: could genetic factors be relevant in the clinical course of COVID-19? J. Med. Virol. 93, 357–365 (2021)." href="/articles/s41392-021-00736-8#ref-CR10" id="ref-link-section-d5157390e4332">10</a></sup> Approximately 320–365 out of every 100,000 humans possess SNVs decreasing spike binding, while 4–12 of every 100,000 humans possess SNVs increasing spike binding. Specific SNVs affecting S protein binding are more abundant in individuals of a certain ancestry, and this frequency may vary six-fold between different ancestries.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 199" title="Heinzelman, P. & Romero, P. A. Discovery of human ACE2 variants with altered recognition by the SARS-CoV-2 spike protein. PLoS One 16, e0251585 (2021)." href="/articles/s41392-021-00736-8#ref-CR199" id="ref-link-section-d5157390e4336">199</a></sup></p><p>Furthermore, the <i>ACE2</i> gene, mapped at the pseudoautosomal regions of X-chromosome, could escape XCI more probably, which likely confers females a double ACE2 dosage to compensate for the loss of membrane ACE2 due to SARS-CoV-2.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 175" title="Viveiros, A. et al. Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones. Am. J. Physiol. Heart Circ. Physiol. 320, H296–H304 (2021)." href="/articles/s41392-021-00736-8#ref-CR175" id="ref-link-section-d5157390e4345">175</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 178" title="Kelada, M., Anto, A., Dave, K. & Saleh, S. N. The role of sex in the risk of mortality from COVID-19 amongst adult patients: a systematic review. Cureus 12, e10114 (2020)." href="/articles/s41392-021-00736-8#ref-CR178" id="ref-link-section-d5157390e4348">178</a></sup> One study showed that, in the hemizygous state, >50% of the variants probably influence the binding of the human ACE2 and the viral S1 protein.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 184" title="Darbani, B. The expression and polymorphism of entry machinery for COVID-19 in human: juxtaposing population groups, gender, and different tissues. Int. J. Environ. Res. Public Health 17, 3433 (2020)." href="/articles/s41392-021-00736-8#ref-CR184" id="ref-link-section-d5157390e4352">184</a></sup> <i>ACE2</i> interaction-booster and interaction-inhibitor variants can be more significant in males and the former may result in a higher mortality rate in males than females.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="von der Thüsen, J. & van der Eerden, M. Histopathology and genetic susceptibility in COVID-19 pneumonia. Eur. J. Clin. Invest. 50, e13259 (2020)." href="/articles/s41392-021-00736-8#ref-CR100" id="ref-link-section-d5157390e4359">100</a></sup> The fact that the <i>ACE2</i> gene expression could be elevated in females due to a skewed XCI, providing a larger ACE2 pool to maintain the fundamental balance of RAAS-regulatory axis in multiple organs after viral infection, could partly explain the lower frequency of severe COVID-19 in females than males.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Gómez, J. et al. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. Gene 762, 145102 (2020)." href="/articles/s41392-021-00736-8#ref-CR17" id="ref-link-section-d5157390e4367">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 172" title="Foresta, C. & Rocca, M. S. & Di Nisio, A. Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome. J. Endocrinol. Invest. 16, 1–6 (2020)." href="/articles/s41392-021-00736-8#ref-CR172" id="ref-link-section-d5157390e4370">172</a></sup></p><h3 class="c-article__sub-heading" id="Sec24">Xq12 and the androgen receptor gene (<i>AR</i>)</h3><p>The 15-bp <i>AR</i> binding element is the critical part of the <i>TMPRSS2</i> promoter for androgen’s binding and its transcription regulation.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 200" title="McCoy, J. et al. Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19? J. Cosmet. Dermatol. 19, 1542–1543 (2020)." href="/articles/s41392-021-00736-8#ref-CR200" id="ref-link-section-d5157390e4391">200</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 201" title="Carethers, J. M. Insights into disparities observed with COVID-19. J. Intern. Med. 289, 463–473 (2020)." href="/articles/s41392-021-00736-8#ref-CR201" id="ref-link-section-d5157390e4394">201</a></sup> This <i>AR</i> element is a polymorphic unit with CAG trinucleotide repeat length variations in the <i>AR</i> gene’s first exon.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 202" title="Wambier, C. G. et al. Androgen sensitivity gateway to COVID-19 disease severity. Drug Dev. Res. 81, 771–776 (2020)." href="/articles/s41392-021-00736-8#ref-CR202" id="ref-link-section-d5157390e4405">202</a></sup> Length variation can determine both transcriptional activity and androgen resistance strength that shorter CAG repeat polymorphism may lead to <i>TMPRSS2</i> overexpression and link to androgen sensitivity, as well as more severe COVID-19.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 176" title="Gadi, N., Wu, S. C., Spihlman, A. P. & Moulton, V. R. What’s sex got to do with COVID-19? Gender-based differences in the host immune response to coronaviruses. Front. Immunol. 11, 2147 (2020)." href="/articles/s41392-021-00736-8#ref-CR176" id="ref-link-section-d5157390e4412">176</a></sup> The variation of greater COVID-19 mortality in males than females or infants of either gender may be explained by androgen-mediated <i>ACE2</i> and <i>TMPRSS2</i> expressions.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Gebhard, C., Regitz-Zagrosek, V., Neuhauser, H. K., Morgan, R. & Klein, S. L. Impact of sex and gender on COVID-19 outcomes in Europe. Biol. Sex Differ. 11, 29 (2020)." href="/articles/s41392-021-00736-8#ref-CR101" id="ref-link-section-d5157390e4422">101</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 200" title="McCoy, J. et al. Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19? J. Cosmet. Dermatol. 19, 1542–1543 (2020)." href="/articles/s41392-021-00736-8#ref-CR200" id="ref-link-section-d5157390e4425">200</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 203" title="Mjaess, G., Karam, A., Aoun, F., Albisinni, S. & Roumeguère, T. COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor. Prog. Urol. 30, 484–487 (2020)." href="/articles/s41392-021-00736-8#ref-CR203" id="ref-link-section-d5157390e4428">203</a></sup> Ethnicity-based vulnerability may be explained by the <i>AR</i> gene polymorphisms that African-American males with shorter CAG repeat lengths have a disproportionate mortality rate than non-Hispanic white males.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 201" title="Carethers, J. M. Insights into disparities observed with COVID-19. J. Intern. Med. 289, 463–473 (2020)." href="/articles/s41392-021-00736-8#ref-CR201" id="ref-link-section-d5157390e4436">201</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 202" title="Wambier, C. G. et al. Androgen sensitivity gateway to COVID-19 disease severity. Drug Dev. Res. 81, 771–776 (2020)." href="/articles/s41392-021-00736-8#ref-CR202" id="ref-link-section-d5157390e4439">202</a></sup></p></div></div></section><section data-title="Conclusions and perspectives"><div class="c-article-section" id="Sec25-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec25">Conclusions and perspectives</h2><div class="c-article-section__content" id="Sec25-content"><p>The world is still suffering from the COVID-19 outbreak and the ultimate outcomes are, so far, unmeasurable, but the global economic, social, and political disruptions caused by this pandemic are poised to worsen in the foreseeable future.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Rajarshi, K. et al. Essential functional molecules associated with SARS-CoV-2 infection: potential therapeutic targets for COVID-19. Gene 768, 145313 (2021)." href="/articles/s41392-021-00736-8#ref-CR11" id="ref-link-section-d5157390e4451">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 204" title="Sironi, M. et al. SARS-CoV-2 and COVID-19: a genetic, epidemiological, and evolutionary perspective. Infect. Genet. Evol. 84, 104384 (2020)." href="/articles/s41392-021-00736-8#ref-CR204" id="ref-link-section-d5157390e4454">204</a></sup> Therefore, understanding the causal relationships between host genetic basis and COVID-19 is urgently needed to identify biomarkers for individuals at high risk, which might also provide potential targets for therapy.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Hu, J., Li, C., Wang, S., Li, T. & Zhang, H. Genetic variants are identified to increase risk of COVID-19 related mortality from UK biobank data. Hum. Genomics 15, 10 (2021)." href="/articles/s41392-021-00736-8#ref-CR6" id="ref-link-section-d5157390e4458">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Ramos-Lopez, O. et al. Exploring host genetic polymorphisms involved in SARS-CoV infection outcomes: implications for personalized medicine in COVID-19. Int. J. Genomics 2020, 6901217 (2020)." href="/articles/s41392-021-00736-8#ref-CR98" id="ref-link-section-d5157390e4461">98</a></sup> Focusing on these variants, which relate to disease susceptibility and severity through viral trafficking pathways or drug curative effect, could better identify risk subjects and effectively control the disease. Large data consortiums are organizing to produce, share, and analyze data, such as the COVID19 Host Genetics Initiative and the COVID Human Genetic Effort.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Ovsyannikova, I. G., Haralambieva, I. H., Crooke, S. N., Poland, G. A. & Kennedy, R. B. The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity. Immunol. Rev. 296, 205–219 (2020)." href="/articles/s41392-021-00736-8#ref-CR12" id="ref-link-section-d5157390e4465">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 205" title="COVID-19 Host Genetics Initiative. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. Eur. J. Hum. Genet. 28, 715–718 (2020)." href="/articles/s41392-021-00736-8#ref-CR205" id="ref-link-section-d5157390e4468">205</a></sup> As more host genetic factors associated with COVID-19 are identified, it should become possible to create tests that would predict the susceptible populations and allow for classifying and safeguarding them.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 190" title="Iyer, G. R. et al. Infectivity and progression of COVID-19 based on selected host candidate gene variants. Front. Genet. 11, 861 (2020)." href="/articles/s41392-021-00736-8#ref-CR190" id="ref-link-section-d5157390e4472">190</a></sup> In summary, we extract and review positive results from vast reported papers. However, for a certain variant, large-scale meta-analyses combining data from multiple consistent studies with reliable statistical significance would be helpful to find therapy targets.</p><p>Ongoing investigations into COVID-19 and individual genetic makeup are fueling global research to develop vaccines, prioritize individuals for treatment, and discover potential drug target candidates.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Schurr, T. G. Host genetic factors and susceptibility to SARS-CoV-2 infection. Am. J. Hum. Biol. 32, e23497 (2020)." href="/articles/s41392-021-00736-8#ref-CR95" id="ref-link-section-d5157390e4479">95</a></sup> The antiviral drug Veklury (remdesivir) is the first and the only treatment for COVID-19 approved by the US Food and Drug Administration (<a href="https://www.fda.gov">https://www.fda.gov</a>). Given that remdesivir is a broad-spectrum antiviral drug, better direct-target-based antiviral therapies that intervene in SARS-CoV-2-infected pathways are anticipated.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 206" title="Asselah, T., Durantel, D., Pasmant, E., Lau, G. & Schinazi, R. F. COVID-19: discovery, diagnostics and drug development. J. Hepatol. 74, 168–184 (2021)." href="/articles/s41392-021-00736-8#ref-CR206" id="ref-link-section-d5157390e4490">206</a></sup> Human genetic basis of COVID-19, which is well known to impact disease susceptibility and severity, may offer novel insights into COVID-19 therapies and controls through identifying particular genes and pathways. Large-scale screening of potential targeted drugs and experimental therapeutic studies would be helpful to develop new drugs or discover repurposing opportunities for existing drugs.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 148" title="Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020)." href="/articles/s41392-021-00736-8#ref-CR148" id="ref-link-section-d5157390e4494">148</a></sup> In order to end this century nightmare early, when it comes to ethical considerations and/or societal questions, further investigations should pay attention to (1) ensuring the validity and usefulness of the reported studies, (2) not undermining the necessity of solidarity in the public health action, (3) not affecting individuals’ action ability or making them be discrimination targets, and (4) perfecting genetic information-related legislation.<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 207" title="Milne, R. Societal considerations in host genome testing for COVID-19. Genet. Med. 22, 1464–1466 (2020)." href="/articles/s41392-021-00736-8#ref-CR207" id="ref-link-section-d5157390e4498">207</a></sup></p></div></div></section> </div> <div class="u-mt-32"> <div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">Yoo, J. H. The fight against the 2019-nCoV outbreak: an arduous march has just begun. <i>J. Korean Med. Sci.</i> <b>35</b>, e56 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3346/jkms.2020.35.e56" data-track-item_id="10.3346/jkms.2020.35.e56" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3346%2Fjkms.2020.35.e56" aria-label="Article reference 1" data-doi="10.3346/jkms.2020.35.e56">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31997618" aria-label="PubMed reference 1">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995816" aria-label="PubMed Central reference 1">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 1" href="http://scholar.google.com/scholar_lookup?&title=The%20fight%20against%20the%202019-nCoV%20outbreak%3A%20an%20arduous%20march%20has%20just%20begun&journal=J.%20Korean%20Med.%20Sci.&doi=10.3346%2Fjkms.2020.35.e56&volume=35&publication_year=2020&author=Yoo%2CJH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="2."><p class="c-article-references__text" id="ref-CR2">Lai, C. C., Shih, T. P., Ko, W. C., Tang, H. J. & Hsueh, P. R. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. <i>Int. J. Antimicrob. Agents</i> <b>55</b>, 105924 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.ijantimicag.2020.105924" data-track-item_id="10.1016/j.ijantimicag.2020.105924" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.ijantimicag.2020.105924" aria-label="Article reference 2" data-doi="10.1016/j.ijantimicag.2020.105924">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXjs1Ogtr8%3D" aria-label="CAS reference 2">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32081636" aria-label="PubMed reference 2">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127800" aria-label="PubMed Central reference 2">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 2" href="http://scholar.google.com/scholar_lookup?&title=Severe%20acute%20respiratory%20syndrome%20coronavirus%202%20%28SARS-CoV-2%29%20and%20coronavirus%20disease-2019%20%28COVID-19%29%3A%20the%20epidemic%20and%20the%20challenges&journal=Int.%20J.%20Antimicrob.%20Agents&doi=10.1016%2Fj.ijantimicag.2020.105924&volume=55&publication_year=2020&author=Lai%2CCC&author=Shih%2CTP&author=Ko%2CWC&author=Tang%2CHJ&author=Hsueh%2CPR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="3."><p class="c-article-references__text" id="ref-CR3">Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. <i>N. Engl. J. Med.</i> <b>382</b>, 727–733 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1056/NEJMoa2001017" data-track-item_id="10.1056/NEJMoa2001017" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1056%2FNEJMoa2001017" aria-label="Article reference 3" data-doi="10.1056/NEJMoa2001017">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXjslGmsrc%3D" aria-label="CAS reference 3">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31978945" aria-label="PubMed reference 3">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092803" aria-label="PubMed Central reference 3">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 3" href="http://scholar.google.com/scholar_lookup?&title=A%20novel%20coronavirus%20from%20patients%20with%20pneumonia%20in%20China%2C%202019&journal=N.%20Engl.%20J.%20Med.&doi=10.1056%2FNEJMoa2001017&volume=382&pages=727-733&publication_year=2020&author=Zhu%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="4."><p class="c-article-references__text" id="ref-CR4">Ravaioli, S. et al. ACE2 and TMPRSS2 potential involvement in genetic susceptibility to SARS-CoV-2 in cancer patients. <i>Cell Transplant.</i> <b>29</b>, 963689720968749 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1177/0963689720968749" data-track-item_id="10.1177/0963689720968749" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1177%2F0963689720968749" aria-label="Article reference 4" data-doi="10.1177/0963689720968749">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33108902" aria-label="PubMed reference 4">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 4" href="http://scholar.google.com/scholar_lookup?&title=ACE2%20and%20TMPRSS2%20potential%20involvement%20in%20genetic%20susceptibility%20to%20SARS-CoV-2%20in%20cancer%20patients&journal=Cell%20Transplant.&doi=10.1177%2F0963689720968749&volume=29&publication_year=2020&author=Ravaioli%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="5."><p class="c-article-references__text" id="ref-CR5">Gorbalenya, A. E. et al. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. <i>Nat. Microbiol.</i> <b>5</b>, 536–544 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41564-020-0695-z" data-track-item_id="10.1038/s41564-020-0695-z" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41564-020-0695-z" aria-label="Article reference 5" data-doi="10.1038/s41564-020-0695-z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXktFemu7Y%3D" aria-label="CAS reference 5">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 5" href="http://scholar.google.com/scholar_lookup?&title=The%20species%20severe%20acute%20respiratory%20syndrome-related%20coronavirus%3A%20classifying%202019-nCoV%20and%20naming%20it%20SARS-CoV-2&journal=Nat.%20Microbiol.&doi=10.1038%2Fs41564-020-0695-z&volume=5&pages=536-544&publication_year=2020&author=Gorbalenya%2CAE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="6."><p class="c-article-references__text" id="ref-CR6">Hu, J., Li, C., Wang, S., Li, T. & Zhang, H. Genetic variants are identified to increase risk of COVID-19 related mortality from UK biobank data. <i>Hum. Genomics</i> <b>15</b>, 10 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40246-021-00306-7" data-track-item_id="10.1186/s40246-021-00306-7" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40246-021-00306-7" aria-label="Article reference 6" data-doi="10.1186/s40246-021-00306-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXjslWmtrY%3D" aria-label="CAS reference 6">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33536081" aria-label="PubMed reference 6">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856608" aria-label="PubMed Central reference 6">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 6" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20variants%20are%20identified%20to%20increase%20risk%20of%20COVID-19%20related%20mortality%20from%20UK%20biobank%20data&journal=Hum.%20Genomics&doi=10.1186%2Fs40246-021-00306-7&volume=15&publication_year=2021&author=Hu%2CJ&author=Li%2CC&author=Wang%2CS&author=Li%2CT&author=Zhang%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="7."><p class="c-article-references__text" id="ref-CR7">Zbinden-Foncea, H., Francaux, M., Deldicque, L. & Hawley, J. A. Does high cardiorespiratory fitness confer some protection against proinflammatory responses after infection by SARS-CoV-2? <i>Obesity</i> <b>28</b>, 1378–1381 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/oby.22849" data-track-item_id="10.1002/oby.22849" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Foby.22849" aria-label="Article reference 7" data-doi="10.1002/oby.22849">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVCmtLfL" aria-label="CAS reference 7">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32324968" aria-label="PubMed reference 7">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 7" href="http://scholar.google.com/scholar_lookup?&title=Does%20high%20cardiorespiratory%20fitness%20confer%20some%20protection%20against%20proinflammatory%20responses%20after%20infection%20by%20SARS-CoV-2%3F&journal=Obesity&doi=10.1002%2Foby.22849&volume=28&pages=1378-1381&publication_year=2020&author=Zbinden-Foncea%2CH&author=Francaux%2CM&author=Deldicque%2CL&author=Hawley%2CJA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="8."><p class="c-article-references__text" id="ref-CR8">Calcagnile, M. et al. Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 spike protein. <i>Biochimie</i> <b>180</b>, 143–148 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.biochi.2020.11.004" data-track-item_id="10.1016/j.biochi.2020.11.004" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.biochi.2020.11.004" aria-label="Article reference 8" data-doi="10.1016/j.biochi.2020.11.004">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitlGrsbfM" aria-label="CAS reference 8">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33181224" aria-label="PubMed reference 8">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 8" href="http://scholar.google.com/scholar_lookup?&title=Molecular%20docking%20simulation%20reveals%20ACE2%20polymorphisms%20that%20may%20increase%20the%20affinity%20of%20ACE2%20with%20the%20SARS-CoV-2%20spike%20protein&journal=Biochimie&doi=10.1016%2Fj.biochi.2020.11.004&volume=180&pages=143-148&publication_year=2021&author=Calcagnile%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="9."><p class="c-article-references__text" id="ref-CR9">Sakuraba, A., Haider, H. & Sato, T. Population difference in allele frequency of HLA-C*05 and its correlation with COVID-19 mortality. <i>Viruses</i> <b>12</b>, 1333 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/v12111333" data-track-item_id="10.3390/v12111333" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fv12111333" aria-label="Article reference 9" data-doi="10.3390/v12111333">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFOjtrjK" aria-label="CAS reference 9">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699862" aria-label="PubMed Central reference 9">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 9" href="http://scholar.google.com/scholar_lookup?&title=Population%20difference%20in%20allele%20frequency%20of%20HLA-C%2A05%20and%20its%20correlation%20with%20COVID-19%20mortality&journal=Viruses&doi=10.3390%2Fv12111333&volume=12&publication_year=2020&author=Sakuraba%2CA&author=Haider%2CH&author=Sato%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="10."><p class="c-article-references__text" id="ref-CR10">Ikitimur, H. et al. Determining host factors contributing to disease severity in a family cluster of 29 hospitalized SARS-CoV-2 patients: could genetic factors be relevant in the clinical course of COVID-19? <i>J. Med. Virol.</i> <b>93</b>, 357–365 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/jmv.26106" data-track-item_id="10.1002/jmv.26106" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fjmv.26106" aria-label="Article reference 10" data-doi="10.1002/jmv.26106">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitVGqt7nF" aria-label="CAS reference 10">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32492209" aria-label="PubMed reference 10">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 10" href="http://scholar.google.com/scholar_lookup?&title=Determining%20host%20factors%20contributing%20to%20disease%20severity%20in%20a%20family%20cluster%20of%2029%20hospitalized%20SARS-CoV-2%20patients%3A%20could%20genetic%20factors%20be%20relevant%20in%20the%20clinical%20course%20of%20COVID-19%3F&journal=J.%20Med.%20Virol.&doi=10.1002%2Fjmv.26106&volume=93&pages=357-365&publication_year=2021&author=Ikitimur%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="11."><p class="c-article-references__text" id="ref-CR11">Rajarshi, K. et al. Essential functional molecules associated with SARS-CoV-2 infection: potential therapeutic targets for COVID-19. <i>Gene</i> <b>768</b>, 145313 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.gene.2020.145313" data-track-item_id="10.1016/j.gene.2020.145313" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.gene.2020.145313" aria-label="Article reference 11" data-doi="10.1016/j.gene.2020.145313">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisVWis7vE" aria-label="CAS reference 11">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33220345" aria-label="PubMed reference 11">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 11" href="http://scholar.google.com/scholar_lookup?&title=Essential%20functional%20molecules%20associated%20with%20SARS-CoV-2%20infection%3A%20potential%20therapeutic%20targets%20for%20COVID-19&journal=Gene&doi=10.1016%2Fj.gene.2020.145313&volume=768&publication_year=2021&author=Rajarshi%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="12."><p class="c-article-references__text" id="ref-CR12">Ovsyannikova, I. G., Haralambieva, I. H., Crooke, S. N., Poland, G. A. & Kennedy, R. B. The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity. <i>Immunol. Rev.</i> <b>296</b>, 205–219 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/imr.12897" data-track-item_id="10.1111/imr.12897" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fimr.12897" aria-label="Article reference 12" data-doi="10.1111/imr.12897">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtl2rsr3K" aria-label="CAS reference 12">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32658335" aria-label="PubMed reference 12">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404857" aria-label="PubMed Central reference 12">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 12" href="http://scholar.google.com/scholar_lookup?&title=The%20role%20of%20host%20genetics%20in%20the%20immune%20response%20to%20SARS-CoV-2%20and%20COVID-19%20susceptibility%20and%20severity&journal=Immunol.%20Rev.&doi=10.1111%2Fimr.12897&volume=296&pages=205-219&publication_year=2020&author=Ovsyannikova%2CIG&author=Haralambieva%2CIH&author=Crooke%2CSN&author=Poland%2CGA&author=Kennedy%2CRB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="13."><p class="c-article-references__text" id="ref-CR13">Williams, F. M. K. et al. Self-reported symptoms of COVID-19, including symptoms most predictive of SARS-CoV-2 infection, are heritable. <i>Twin Res. Hum. Genet.</i> <b>23</b>, 316–321 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1017/thg.2020.85" data-track-item_id="10.1017/thg.2020.85" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1017%2Fthg.2020.85" aria-label="Article reference 13" data-doi="10.1017/thg.2020.85">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33558003" aria-label="PubMed reference 13">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 13" href="http://scholar.google.com/scholar_lookup?&title=Self-reported%20symptoms%20of%20COVID-19%2C%20including%20symptoms%20most%20predictive%20of%20SARS-CoV-2%20infection%2C%20are%20heritable&journal=Twin%20Res.%20Hum.%20Genet.&doi=10.1017%2Fthg.2020.85&volume=23&pages=316-321&publication_year=2020&author=Williams%2CFMK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="14."><p class="c-article-references__text" id="ref-CR14">Agrawal, H. et al. An assessment on impact of COVID-19 infection in a gender specific manner. <i>Stem Cell Rev. Rep.</i> <b>17</b>, 94–112 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s12015-020-10048-z" data-track-item_id="10.1007/s12015-020-10048-z" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s12015-020-10048-z" aria-label="Article reference 14" data-doi="10.1007/s12015-020-10048-z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitVyiur%2FL" aria-label="CAS reference 14">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33029768" aria-label="PubMed reference 14">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 14" href="http://scholar.google.com/scholar_lookup?&title=An%20assessment%20on%20impact%20of%20COVID-19%20infection%20in%20a%20gender%20specific%20manner&journal=Stem%20Cell%20Rev.%20Rep.&doi=10.1007%2Fs12015-020-10048-z&volume=17&pages=94-112&publication_year=2021&author=Agrawal%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="15."><p class="c-article-references__text" id="ref-CR15">Zhao, J. et al. Relationship between the ABO blood group and the coronavirus disease 2019 (COVID-19) susceptibility. <i>Clin. Infect. Dis.</i> <b>73</b>, 328–331 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/cid/ciaa1150" data-track-item_id="10.1093/cid/ciaa1150" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fcid%2Fciaa1150" aria-label="Article reference 15" data-doi="10.1093/cid/ciaa1150">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhs1WqurzO" aria-label="CAS reference 15">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32750119" aria-label="PubMed reference 15">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 15" href="http://scholar.google.com/scholar_lookup?&title=Relationship%20between%20the%20ABO%20blood%20group%20and%20the%20coronavirus%20disease%202019%20%28COVID-19%29%20susceptibility&journal=Clin.%20Infect.%20Dis.&doi=10.1093%2Fcid%2Fciaa1150&volume=73&pages=328-331&publication_year=2021&author=Zhao%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="16."><p class="c-article-references__text" id="ref-CR16">Nguyen, A. et al. Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2. <i>J. Virol</i>. <b>94</b> e00510–20 (2020).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="17."><p class="c-article-references__text" id="ref-CR17">Gómez, J. et al. Angiotensin-converting enzymes (ACE, ACE2) gene variants and COVID-19 outcome. <i>Gene</i> <b>762</b>, 145102 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.gene.2020.145102" data-track-item_id="10.1016/j.gene.2020.145102" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.gene.2020.145102" aria-label="Article reference 17" data-doi="10.1016/j.gene.2020.145102">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32882331" aria-label="PubMed reference 17">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456966" aria-label="PubMed Central reference 17">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhslGhtLzM" aria-label="CAS reference 17">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 17" href="http://scholar.google.com/scholar_lookup?&title=Angiotensin-converting%20enzymes%20%28ACE%2C%20ACE2%29%20gene%20variants%20and%20COVID-19%20outcome&journal=Gene&doi=10.1016%2Fj.gene.2020.145102&volume=762&publication_year=2020&author=G%C3%B3mez%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="18."><p class="c-article-references__text" id="ref-CR18">Rahimi, A., Mirzazadeh, A. & Tavakolpour, S. Genetics and genomics of SARS-CoV-2: a review of the literature with the special focus on genetic diversity and SARS-CoV-2 genome detection. <i>Genomics</i> <b>113</b>, 1221–1232 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.ygeno.2020.09.059" data-track-item_id="10.1016/j.ygeno.2020.09.059" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.ygeno.2020.09.059" aria-label="Article reference 18" data-doi="10.1016/j.ygeno.2020.09.059">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitFagsLbN" aria-label="CAS reference 18">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33007398" aria-label="PubMed reference 18">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 18" href="http://scholar.google.com/scholar_lookup?&title=Genetics%20and%20genomics%20of%20SARS-CoV-2%3A%20a%20review%20of%20the%20literature%20with%20the%20special%20focus%20on%20genetic%20diversity%20and%20SARS-CoV-2%20genome%20detection&journal=Genomics&doi=10.1016%2Fj.ygeno.2020.09.059&volume=113&pages=1221-1232&publication_year=2021&author=Rahimi%2CA&author=Mirzazadeh%2CA&author=Tavakolpour%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="19."><p class="c-article-references__text" id="ref-CR19">Nascimento, V. A. D. et al. Genomic and phylogenetic characterisation of an imported case of SARS-CoV-2 in Amazonas State, Brazil. <i>Mem. Inst. Oswaldo Cruz</i> <b>115</b>, e200310 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1590/0074-02760200310" data-track-item_id="10.1590/0074-02760200310" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1590%2F0074-02760200310" aria-label="Article reference 19" data-doi="10.1590/0074-02760200310">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFygurrO" aria-label="CAS reference 19">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32997001" aria-label="PubMed reference 19">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523504" aria-label="PubMed Central reference 19">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 19" href="http://scholar.google.com/scholar_lookup?&title=Genomic%20and%20phylogenetic%20characterisation%20of%20an%20imported%20case%20of%20SARS-CoV-2%20in%20Amazonas%20State%2C%20Brazil&journal=Mem.%20Inst.%20Oswaldo%20Cruz&doi=10.1590%2F0074-02760200310&volume=115&publication_year=2020&author=Nascimento%2CVAD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="20."><p class="c-article-references__text" id="ref-CR20">Dobrindt, K. et al. Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection. <i>Stem Cell Rep.</i> <b>16</b>, 505–518 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.stemcr.2021.02.010" data-track-item_id="10.1016/j.stemcr.2021.02.010" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.stemcr.2021.02.010" aria-label="Article reference 20" data-doi="10.1016/j.stemcr.2021.02.010">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXls1ertb4%3D" aria-label="CAS reference 20">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 20" href="http://scholar.google.com/scholar_lookup?&title=Common%20genetic%20variation%20in%20humans%20impacts%20in%20vitro%20susceptibility%20to%20SARS-CoV-2%20infection&journal=Stem%20Cell%20Rep.&doi=10.1016%2Fj.stemcr.2021.02.010&volume=16&pages=505-518&publication_year=2021&author=Dobrindt%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="21."><p class="c-article-references__text" id="ref-CR21">Jutzeler, C. R. et al. Comorbidities, clinical signs and symptoms, laboratory findings, imaging features, treatment strategies, and outcomes in adult and pediatric patients with COVID-19: a systematic review and meta-analysis. <i>Travel Med. Infect. Dis.</i> <b>37</b>, 101825 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.tmaid.2020.101825" data-track-item_id="10.1016/j.tmaid.2020.101825" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.tmaid.2020.101825" aria-label="Article reference 21" data-doi="10.1016/j.tmaid.2020.101825">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32763496" aria-label="PubMed reference 21">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402237" aria-label="PubMed Central reference 21">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 21" href="http://scholar.google.com/scholar_lookup?&title=Comorbidities%2C%20clinical%20signs%20and%20symptoms%2C%20laboratory%20findings%2C%20imaging%20features%2C%20treatment%20strategies%2C%20and%20outcomes%20in%20adult%20and%20pediatric%20patients%20with%20COVID-19%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Travel%20Med.%20Infect.%20Dis.&doi=10.1016%2Fj.tmaid.2020.101825&volume=37&publication_year=2020&author=Jutzeler%2CCR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="22."><p class="c-article-references__text" id="ref-CR22">Pormohammad, A. et al. Clinical characteristics, laboratory findings, radiographic signs and outcomes of 61,742 patients with confirmed COVID-19 infection: a systematic review and meta-analysis. <i>Microb. Pathog.</i> <b>147</b>, 104390 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.micpath.2020.104390" data-track-item_id="10.1016/j.micpath.2020.104390" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.micpath.2020.104390" aria-label="Article reference 22" data-doi="10.1016/j.micpath.2020.104390">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVWgsL7O" aria-label="CAS reference 22">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32681968" aria-label="PubMed reference 22">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361116" aria-label="PubMed Central reference 22">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 22" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20characteristics%2C%20laboratory%20findings%2C%20radiographic%20signs%20and%20outcomes%20of%2061%2C742%20patients%20with%20confirmed%20COVID-19%20infection%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Microb.%20Pathog.&doi=10.1016%2Fj.micpath.2020.104390&volume=147&publication_year=2020&author=Pormohammad%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="23."><p class="c-article-references__text" id="ref-CR23">Wang, C., Horby, P. W., Hayden, F. G. & Gao, G. F. A novel coronavirus outbreak of global health concern. <i>Lancet</i> <b>395</b>, 470–473 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0140-6736(20)30185-9" data-track-item_id="10.1016/S0140-6736(20)30185-9" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0140-6736%2820%2930185-9" aria-label="Article reference 23" data-doi="10.1016/S0140-6736(20)30185-9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXnsVaisLg%3D" aria-label="CAS reference 23">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31986257" aria-label="PubMed reference 23">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135038" aria-label="PubMed Central reference 23">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 23" href="http://scholar.google.com/scholar_lookup?&title=A%20novel%20coronavirus%20outbreak%20of%20global%20health%20concern&journal=Lancet&doi=10.1016%2FS0140-6736%2820%2930185-9&volume=395&pages=470-473&publication_year=2020&author=Wang%2CC&author=Horby%2CPW&author=Hayden%2CFG&author=Gao%2CGF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="24."><p class="c-article-references__text" id="ref-CR24">Shu, T. et al. Plasma proteomics identify biomarkers and pathogenesis of COVID-19. <i>Immunity</i> <b>53</b>, 1108–1122.e5 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.immuni.2020.10.008" data-track-item_id="10.1016/j.immuni.2020.10.008" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.immuni.2020.10.008" aria-label="Article reference 24" data-doi="10.1016/j.immuni.2020.10.008">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit1akurrK" aria-label="CAS reference 24">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33128875" aria-label="PubMed reference 24">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574896" aria-label="PubMed Central reference 24">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 24" href="http://scholar.google.com/scholar_lookup?&title=Plasma%20proteomics%20identify%20biomarkers%20and%20pathogenesis%20of%20COVID-19&journal=Immunity&doi=10.1016%2Fj.immuni.2020.10.008&volume=53&pages=1108-1122.e5&publication_year=2020&author=Shu%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="25."><p class="c-article-references__text" id="ref-CR25">Fu, L. et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. <i>J. Infect.</i> <b>80</b>, 656–665 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jinf.2020.03.041" data-track-item_id="10.1016/j.jinf.2020.03.041" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jinf.2020.03.041" aria-label="Article reference 25" data-doi="10.1016/j.jinf.2020.03.041">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtVantLzE" aria-label="CAS reference 25">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32283155" aria-label="PubMed reference 25">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151416" aria-label="PubMed Central reference 25">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 25" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20characteristics%20of%20coronavirus%20disease%202019%20%28COVID-19%29%20in%20China%3A%20a%20systematic%20review%20and%20meta-analysis&journal=J.%20Infect.&doi=10.1016%2Fj.jinf.2020.03.041&volume=80&pages=656-665&publication_year=2020&author=Fu%2CL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="26."><p class="c-article-references__text" id="ref-CR26">Wong, C. K. H., Wong, J. Y. H., Tang, E. H. M., Au, C. H. & Wai, A. K. C. Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis. <i>Sci. Rep.</i> <b>10</b>, 19765 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41598-020-74988-9" data-track-item_id="10.1038/s41598-020-74988-9" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41598-020-74988-9" aria-label="Article reference 26" data-doi="10.1038/s41598-020-74988-9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitlKlt7zI" aria-label="CAS reference 26">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33188232" aria-label="PubMed reference 26">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666204" aria-label="PubMed Central reference 26">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 26" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20presentations%2C%20laboratory%20and%20radiological%20findings%2C%20and%20treatments%20for%2011%2C028%20COVID-19%20patients%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Sci.%20Rep.&doi=10.1038%2Fs41598-020-74988-9&volume=10&publication_year=2020&author=Wong%2CCKH&author=Wong%2CJYH&author=Tang%2CEHM&author=Au%2CCH&author=Wai%2CAKC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="27."><p class="c-article-references__text" id="ref-CR27">Yang, J. et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. <i>Int. J. Infect. Dis.</i> <b>94</b>, 91–95 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.ijid.2020.03.017" data-track-item_id="10.1016/j.ijid.2020.03.017" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.ijid.2020.03.017" aria-label="Article reference 27" data-doi="10.1016/j.ijid.2020.03.017">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXnslOgsrY%3D" aria-label="CAS reference 27">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32173574" aria-label="PubMed reference 27">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194638" aria-label="PubMed Central reference 27">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 27" href="http://scholar.google.com/scholar_lookup?&title=Prevalence%20of%20comorbidities%20and%20its%20effects%20in%20patients%20infected%20with%20SARS-CoV-2%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Int.%20J.%20Infect.%20Dis.&doi=10.1016%2Fj.ijid.2020.03.017&volume=94&pages=91-95&publication_year=2020&author=Yang%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="28."><p class="c-article-references__text" id="ref-CR28">Li, L. Q. et al. COVID-19 patients’ clinical characteristics, discharge rate, and fatality rate of meta-analysis. <i>J. Med. Virol.</i> <b>92</b>, 577–583 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/jmv.25757" data-track-item_id="10.1002/jmv.25757" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fjmv.25757" aria-label="Article reference 28" data-doi="10.1002/jmv.25757">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXntlels7k%3D" aria-label="CAS reference 28">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32162702" aria-label="PubMed reference 28">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 28" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20patients%E2%80%99%20clinical%20characteristics%2C%20discharge%20rate%2C%20and%20fatality%20rate%20of%20meta-analysis&journal=J.%20Med.%20Virol.&doi=10.1002%2Fjmv.25757&volume=92&pages=577-583&publication_year=2020&author=Li%2CLQ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="29."><p class="c-article-references__text" id="ref-CR29">Ghayda, R. A. et al. Correlations of clinical and laboratory characteristics of COVID-19: a systematic review and meta-analysis. <i>Int. J. Environ. Res. Public Health</i> <b>17</b>, 5026 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/ijerph17145026" data-track-item_id="10.3390/ijerph17145026" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fijerph17145026" aria-label="Article reference 29" data-doi="10.3390/ijerph17145026">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitVWgurrM" aria-label="CAS reference 29">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400047" aria-label="PubMed Central reference 29">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 29" href="http://scholar.google.com/scholar_lookup?&title=Correlations%20of%20clinical%20and%20laboratory%20characteristics%20of%20COVID-19%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Int.%20J.%20Environ.%20Res.%20Public%20Health&doi=10.3390%2Fijerph17145026&volume=17&publication_year=2020&author=Ghayda%2CRA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="30."><p class="c-article-references__text" id="ref-CR30">Chua, T. H., Xu, Z. & King, N. K. K. Neurological manifestations in COVID-19: a systematic review and meta-analysis. <i>Brain Inj.</i> <b>34</b>, 1549–1568 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1080/02699052.2020.1831606" data-track-item_id="10.1080/02699052.2020.1831606" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1080%2F02699052.2020.1831606" aria-label="Article reference 30" data-doi="10.1080/02699052.2020.1831606">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33074036" aria-label="PubMed reference 30">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 30" href="http://scholar.google.com/scholar_lookup?&title=Neurological%20manifestations%20in%20COVID-19%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Brain%20Inj.&doi=10.1080%2F02699052.2020.1831606&volume=34&pages=1549-1568&publication_year=2020&author=Chua%2CTH&author=Xu%2CZ&author=King%2CNKK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="31."><p class="c-article-references__text" id="ref-CR31">Makhoul, K. & Jankovic, J. Parkinson’s disease after COVID-19. <i>J. Neurol. Sci.</i> <b>422</b>, 117331 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jns.2021.117331" data-track-item_id="10.1016/j.jns.2021.117331" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jns.2021.117331" aria-label="Article reference 31" data-doi="10.1016/j.jns.2021.117331">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXjslWntr8%3D" aria-label="CAS reference 31">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33540185" aria-label="PubMed reference 31">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 31" href="http://scholar.google.com/scholar_lookup?&title=Parkinson%E2%80%99s%20disease%20after%20COVID-19&journal=J.%20Neurol.%20Sci.&doi=10.1016%2Fj.jns.2021.117331&volume=422&publication_year=2021&author=Makhoul%2CK&author=Jankovic%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="32."><p class="c-article-references__text" id="ref-CR32">Singhal, T. A review of coronavirus disease-2019 (COVID-19). <i>Indian J. Pediatr.</i> <b>87</b>, 281–286 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s12098-020-03263-6" data-track-item_id="10.1007/s12098-020-03263-6" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s12098-020-03263-6" aria-label="Article reference 32" data-doi="10.1007/s12098-020-03263-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32166607" aria-label="PubMed reference 32">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090728" aria-label="PubMed Central reference 32">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 32" href="http://scholar.google.com/scholar_lookup?&title=A%20review%20of%20coronavirus%20disease-2019%20%28COVID-19%29&journal=Indian%20J.%20Pediatr.&doi=10.1007%2Fs12098-020-03263-6&volume=87&pages=281-286&publication_year=2020&author=Singhal%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="33."><p class="c-article-references__text" id="ref-CR33">Harrison, A. G., Lin, T. & Wang, P. Mechanisms of SARS-CoV-2 transmission and pathogenesis. <i>Trends Immunol.</i> <b>41</b>, 1100–1115 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.it.2020.10.004" data-track-item_id="10.1016/j.it.2020.10.004" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.it.2020.10.004" aria-label="Article reference 33" data-doi="10.1016/j.it.2020.10.004">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitFWisLvN" aria-label="CAS reference 33">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33132005" aria-label="PubMed reference 33">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556779" aria-label="PubMed Central reference 33">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 33" href="http://scholar.google.com/scholar_lookup?&title=Mechanisms%20of%20SARS-CoV-2%20transmission%20and%20pathogenesis&journal=Trends%20Immunol.&doi=10.1016%2Fj.it.2020.10.004&volume=41&pages=1100-1115&publication_year=2020&author=Harrison%2CAG&author=Lin%2CT&author=Wang%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="34."><p class="c-article-references__text" id="ref-CR34">Hossain, M. F. et al. COVID-19 outbreak: pathogenesis, current therapies, and potentials for future management. <i>Front. Pharm.</i> <b>11</b>, 563478 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fphar.2020.563478" data-track-item_id="10.3389/fphar.2020.563478" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffphar.2020.563478" aria-label="Article reference 34" data-doi="10.3389/fphar.2020.563478">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXjslyqu7c%3D" aria-label="CAS reference 34">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 34" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20outbreak%3A%20pathogenesis%2C%20current%20therapies%2C%20and%20potentials%20for%20future%20management&journal=Front.%20Pharm.&doi=10.3389%2Ffphar.2020.563478&volume=11&publication_year=2020&author=Hossain%2CMF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="35."><p class="c-article-references__text" id="ref-CR35">Simoneau, C. R. & Ott, M. Modeling multi-organ infection by SARS-CoV-2 using stem cell technology. <i>Cell Stem Cell</i> <b>27</b>, 859–868 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.stem.2020.11.012" data-track-item_id="10.1016/j.stem.2020.11.012" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.stem.2020.11.012" aria-label="Article reference 35" data-doi="10.1016/j.stem.2020.11.012">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFSltr7N" aria-label="CAS reference 35">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33275899" aria-label="PubMed reference 35">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713543" aria-label="PubMed Central reference 35">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 35" href="http://scholar.google.com/scholar_lookup?&title=Modeling%20multi-organ%20infection%20by%20SARS-CoV-2%20using%20stem%20cell%20technology&journal=Cell%20Stem%20Cell&doi=10.1016%2Fj.stem.2020.11.012&volume=27&pages=859-868&publication_year=2020&author=Simoneau%2CCR&author=Ott%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="36."><p class="c-article-references__text" id="ref-CR36">Hu, J. & Wang, Y. The clinical characteristics and risk factors of severe COVID-19. <i>Gerontology</i> <b>6</b>, 1–12 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 36" href="http://scholar.google.com/scholar_lookup?&title=The%20clinical%20characteristics%20and%20risk%20factors%20of%20severe%20COVID-19&journal=Gerontology&volume=6&pages=1-12&publication_year=2021&author=Hu%2CJ&author=Wang%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="37."><p class="c-article-references__text" id="ref-CR37">Kronbichler, A. et al. Asymptomatic patients as a source of COVID-19 infections: a systematic review and meta-analysis. <i>Int. J. Infect. Dis.</i> <b>98</b>, 180–186 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.ijid.2020.06.052" data-track-item_id="10.1016/j.ijid.2020.06.052" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.ijid.2020.06.052" aria-label="Article reference 37" data-doi="10.1016/j.ijid.2020.06.052">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVKksbbP" aria-label="CAS reference 37">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32562846" aria-label="PubMed reference 37">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832751" aria-label="PubMed Central reference 37">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 37" href="http://scholar.google.com/scholar_lookup?&title=Asymptomatic%20patients%20as%20a%20source%20of%20COVID-19%20infections%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Int.%20J.%20Infect.%20Dis.&doi=10.1016%2Fj.ijid.2020.06.052&volume=98&pages=180-186&publication_year=2020&author=Kronbichler%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="38."><p class="c-article-references__text" id="ref-CR38">Wan, S. et al. CT manifestations and clinical characteristics of 1115 patients with coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. <i>Acad. Radiol.</i> <b>27</b>, 910–921 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.acra.2020.04.033" data-track-item_id="10.1016/j.acra.2020.04.033" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.acra.2020.04.033" aria-label="Article reference 38" data-doi="10.1016/j.acra.2020.04.033">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32505599" aria-label="PubMed reference 38">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200137" aria-label="PubMed Central reference 38">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 38" href="http://scholar.google.com/scholar_lookup?&title=CT%20manifestations%20and%20clinical%20characteristics%20of%201115%20patients%20with%20coronavirus%20disease%202019%20%28COVID-19%29%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Acad.%20Radiol.&doi=10.1016%2Fj.acra.2020.04.033&volume=27&pages=910-921&publication_year=2020&author=Wan%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="39."><p class="c-article-references__text" id="ref-CR39">Yang, H., Lan, Y., Yao, X., Lin, S. & Xie, B. The chest CT features of coronavirus disease 2019 (COVID-19) in China: a meta-analysis of 19 retrospective studies. <i>Virol. J.</i> <b>17</b>, 159 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12985-020-01432-9" data-track-item_id="10.1186/s12985-020-01432-9" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12985-020-01432-9" aria-label="Article reference 39" data-doi="10.1186/s12985-020-01432-9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33087181" aria-label="PubMed reference 39">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576554" aria-label="PubMed Central reference 39">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitFymt7%2FP" aria-label="CAS reference 39">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 39" href="http://scholar.google.com/scholar_lookup?&title=The%20chest%20CT%20features%20of%20coronavirus%20disease%202019%20%28COVID-19%29%20in%20China%3A%20a%20meta-analysis%20of%2019%20retrospective%20studies&journal=Virol.%20J.&doi=10.1186%2Fs12985-020-01432-9&volume=17&publication_year=2020&author=Yang%2CH&author=Lan%2CY&author=Yao%2CX&author=Lin%2CS&author=Xie%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="40."><p class="c-article-references__text" id="ref-CR40">Muhammad, S. Z. et al. Chest computed tomography findings in hospitalized COVID-19 patients: a systematic review and meta-analysis. <i>Infez. Med.</i> <b>28</b>, 295–301 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhvFWrtL7N" aria-label="CAS reference 40">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32920564" aria-label="PubMed reference 40">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 40" href="http://scholar.google.com/scholar_lookup?&title=Chest%20computed%20tomography%20findings%20in%20hospitalized%20COVID-19%20patients%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Infez.%20Med.&volume=28&pages=295-301&publication_year=2020&author=Muhammad%2CSZ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="41."><p class="c-article-references__text" id="ref-CR41">Wu, F. et al. A new coronavirus associated with human respiratory disease in China. <i>Nature</i> <b>579</b>, 265–269 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41586-020-2008-3" data-track-item_id="10.1038/s41586-020-2008-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41586-020-2008-3" aria-label="Article reference 41" data-doi="10.1038/s41586-020-2008-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXksFKlsLc%3D" aria-label="CAS reference 41">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32015508" aria-label="PubMed reference 41">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094943" aria-label="PubMed Central reference 41">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 41" href="http://scholar.google.com/scholar_lookup?&title=A%20new%20coronavirus%20associated%20with%20human%20respiratory%20disease%20in%20China&journal=Nature&doi=10.1038%2Fs41586-020-2008-3&volume=579&pages=265-269&publication_year=2020&author=Wu%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="42."><p class="c-article-references__text" id="ref-CR42">Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. <i>Lancet</i> <b>395</b>, 497–506 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0140-6736(20)30183-5" data-track-item_id="10.1016/S0140-6736(20)30183-5" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0140-6736%2820%2930183-5" aria-label="Article reference 42" data-doi="10.1016/S0140-6736(20)30183-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhs1Kqu7c%3D" aria-label="CAS reference 42">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31986264" aria-label="PubMed reference 42">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159299" aria-label="PubMed Central reference 42">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 42" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20features%20of%20patients%20infected%20with%202019%20novel%20coronavirus%20in%20Wuhan%2C%20China&journal=Lancet&doi=10.1016%2FS0140-6736%2820%2930183-5&volume=395&pages=497-506&publication_year=2020&author=Huang%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="43."><p class="c-article-references__text" id="ref-CR43">Khomari, F., Nabi-Afjadi, M., Yarahmadi, S., Eskandari, H. & Bahreini, E. Effects of cell proteostasis network on the survival of SARS-CoV-2. <i>Biol. Proced. Online</i> <b>23</b>, 8 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12575-021-00145-9" data-track-item_id="10.1186/s12575-021-00145-9" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12575-021-00145-9" aria-label="Article reference 43" data-doi="10.1186/s12575-021-00145-9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXls1ert7k%3D" aria-label="CAS reference 43">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33618659" aria-label="PubMed reference 43">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899210" aria-label="PubMed Central reference 43">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 43" href="http://scholar.google.com/scholar_lookup?&title=Effects%20of%20cell%20proteostasis%20network%20on%20the%20survival%20of%20SARS-CoV-2&journal=Biol.%20Proced.%20Online&doi=10.1186%2Fs12575-021-00145-9&volume=23&publication_year=2021&author=Khomari%2CF&author=Nabi-Afjadi%2CM&author=Yarahmadi%2CS&author=Eskandari%2CH&author=Bahreini%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="44."><p class="c-article-references__text" id="ref-CR44">V’kovski, P., Kratzel, A., Steiner, S., Stalder, H. & Thiel, V. Coronavirus biology and replication: implications for SARS-CoV-2. <i>Nat. Rev. Microbiol.</i> <b>19</b>, 155–170 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41579-020-00468-6" data-track-item_id="10.1038/s41579-020-00468-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41579-020-00468-6" aria-label="Article reference 44" data-doi="10.1038/s41579-020-00468-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33116300" aria-label="PubMed reference 44">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit1GjsLjF" aria-label="CAS reference 44">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 44" href="http://scholar.google.com/scholar_lookup?&title=Coronavirus%20biology%20and%20replication%3A%20implications%20for%20SARS-CoV-2&journal=Nat.%20Rev.%20Microbiol.&doi=10.1038%2Fs41579-020-00468-6&volume=19&pages=155-170&publication_year=2021&author=V%E2%80%99kovski%2CP&author=Kratzel%2CA&author=Steiner%2CS&author=Stalder%2CH&author=Thiel%2CV"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="45."><p class="c-article-references__text" id="ref-CR45">Bzówka, M. et al. Structural and evolutionary analysis indicate that the SARS-CoV-2 Mpro is a challenging target for small-molecule inhibitor design. <i>Int. J. Mol. Sci.</i> <b>21</b>, 3099 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/ijms21093099" data-track-item_id="10.3390/ijms21093099" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fijms21093099" aria-label="Article reference 45" data-doi="10.3390/ijms21093099">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247150" aria-label="PubMed Central reference 45">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhvVOjsLvE" aria-label="CAS reference 45">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 45" href="http://scholar.google.com/scholar_lookup?&title=Structural%20and%20evolutionary%20analysis%20indicate%20that%20the%20SARS-CoV-2%20Mpro%20is%20a%20challenging%20target%20for%20small-molecule%20inhibitor%20design&journal=Int.%20J.%20Mol.%20Sci.&doi=10.3390%2Fijms21093099&volume=21&publication_year=2020&author=Bz%C3%B3wka%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="46."><p class="c-article-references__text" id="ref-CR46">Adedokun, K. A., Olarinmoye, A. O., Mustapha, J. O. & Kamorudeen, R. T. A close look at the biology of SARS-CoV-2, and the potential influence of weather conditions and seasons on COVID-19 case spread. <i>Infect. Dis. Poverty</i> <b>9</b>, 77 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40249-020-00688-1" data-track-item_id="10.1186/s40249-020-00688-1" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40249-020-00688-1" aria-label="Article reference 46" data-doi="10.1186/s40249-020-00688-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32586369" aria-label="PubMed reference 46">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316581" aria-label="PubMed Central reference 46">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 46" href="http://scholar.google.com/scholar_lookup?&title=A%20close%20look%20at%20the%20biology%20of%20SARS-CoV-2%2C%20and%20the%20potential%20influence%20of%20weather%20conditions%20and%20seasons%20on%20COVID-19%20case%20spread&journal=Infect.%20Dis.%20Poverty&doi=10.1186%2Fs40249-020-00688-1&volume=9&publication_year=2020&author=Adedokun%2CKA&author=Olarinmoye%2CAO&author=Mustapha%2CJO&author=Kamorudeen%2CRT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="47."><p class="c-article-references__text" id="ref-CR47">Chen, L. et al. RNA based mNGS approach identifies a novel human coronavirus from two individual pneumonia cases in 2019 Wuhan outbreak. <i>Emerg. Microbes Infect.</i> <b>9</b>, 313–319 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1080/22221751.2020.1725399" data-track-item_id="10.1080/22221751.2020.1725399" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1080%2F22221751.2020.1725399" aria-label="Article reference 47" data-doi="10.1080/22221751.2020.1725399">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXotFOktbo%3D" aria-label="CAS reference 47">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32020836" aria-label="PubMed reference 47">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033720" aria-label="PubMed Central reference 47">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 47" href="http://scholar.google.com/scholar_lookup?&title=RNA%20based%20mNGS%20approach%20identifies%20a%20novel%20human%20coronavirus%20from%20two%20individual%20pneumonia%20cases%20in%202019%20Wuhan%20outbreak&journal=Emerg.%20Microbes%20Infect.&doi=10.1080%2F22221751.2020.1725399&volume=9&pages=313-319&publication_year=2020&author=Chen%2CL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="48."><p class="c-article-references__text" id="ref-CR48">Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. <i>Nature</i> <b>579</b>, 270–273 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41586-020-2012-7" data-track-item_id="10.1038/s41586-020-2012-7" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41586-020-2012-7" aria-label="Article reference 48" data-doi="10.1038/s41586-020-2012-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXksFKlsLg%3D" aria-label="CAS reference 48">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32015507" aria-label="PubMed reference 48">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095418" aria-label="PubMed Central reference 48">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 48" href="http://scholar.google.com/scholar_lookup?&title=A%20pneumonia%20outbreak%20associated%20with%20a%20new%20coronavirus%20of%20probable%20bat%20origin&journal=Nature&doi=10.1038%2Fs41586-020-2012-7&volume=579&pages=270-273&publication_year=2020&author=Zhou%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="49."><p class="c-article-references__text" id="ref-CR49">Shereen, M. A., Khan, S., Kazmi, A., Bashir, N. & Siddique, R. COVID-19 infection: origin, transmission, and characteristics of human coronaviruses. <i>J. Adv. Res.</i> <b>24</b>, 91–98 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jare.2020.03.005" data-track-item_id="10.1016/j.jare.2020.03.005" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jare.2020.03.005" aria-label="Article reference 49" data-doi="10.1016/j.jare.2020.03.005">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXmsl2ktbk%3D" aria-label="CAS reference 49">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32257431" aria-label="PubMed reference 49">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113610" aria-label="PubMed Central reference 49">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 49" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20infection%3A%20origin%2C%20transmission%2C%20and%20characteristics%20of%20human%20coronaviruses&journal=J.%20Adv.%20Res.&doi=10.1016%2Fj.jare.2020.03.005&volume=24&pages=91-98&publication_year=2020&author=Shereen%2CMA&author=Khan%2CS&author=Kazmi%2CA&author=Bashir%2CN&author=Siddique%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="50."><p class="c-article-references__text" id="ref-CR50">Morawska, L. & Milton, D. K. It is time to address airborne transmission of coronavirus disease 2019 (COVID-19). <i>Clin. Infect. Dis.</i> <b>71</b>, 2311–2313 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1SgtLjE" aria-label="CAS reference 50">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32628269" aria-label="PubMed reference 50">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 50" href="http://scholar.google.com/scholar_lookup?&title=It%20is%20time%20to%20address%20airborne%20transmission%20of%20coronavirus%20disease%202019%20%28COVID-19%29&journal=Clin.%20Infect.%20Dis.&volume=71&pages=2311-2313&publication_year=2020&author=Morawska%2CL&author=Milton%2CDK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="51."><p class="c-article-references__text" id="ref-CR51">Jin, Y. H. et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). <i>Mil. Med. Res.</i> <b>7</b>, 4 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXns1aht7w%3D" aria-label="CAS reference 51">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32029004" aria-label="PubMed reference 51">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003341" aria-label="PubMed Central reference 51">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 51" href="http://scholar.google.com/scholar_lookup?&title=A%20rapid%20advice%20guideline%20for%20the%20diagnosis%20and%20treatment%20of%202019%20novel%20coronavirus%20%282019-nCoV%29%20infected%20pneumonia%20%28standard%20version%29&journal=Mil.%20Med.%20Res.&volume=7&publication_year=2020&author=Jin%2CYH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="52."><p class="c-article-references__text" id="ref-CR52">Wang, Z. et al. Transmission and prevention of SARS-CoV-2. <i>Biochem. Soc. Trans.</i> <b>48</b>, 2307–2316 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1042/BST20200693" data-track-item_id="10.1042/BST20200693" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1042%2FBST20200693" aria-label="Article reference 52" data-doi="10.1042/BST20200693">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisVyls7fI" aria-label="CAS reference 52">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33084885" aria-label="PubMed reference 52">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 52" href="http://scholar.google.com/scholar_lookup?&title=Transmission%20and%20prevention%20of%20SARS-CoV-2&journal=Biochem.%20Soc.%20Trans.&doi=10.1042%2FBST20200693&volume=48&pages=2307-2316&publication_year=2020&author=Wang%2CZ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="53."><p class="c-article-references__text" id="ref-CR53">Vivanti, A. J. et al. Transplacental transmission of SARS-CoV-2 infection. <i>Nat. Commun.</i> <b>11</b>, 3572 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41467-020-17436-6" data-track-item_id="10.1038/s41467-020-17436-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41467-020-17436-6" aria-label="Article reference 53" data-doi="10.1038/s41467-020-17436-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVSmtrvP" aria-label="CAS reference 53">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32665677" aria-label="PubMed reference 53">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360599" aria-label="PubMed Central reference 53">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 53" href="http://scholar.google.com/scholar_lookup?&title=Transplacental%20transmission%20of%20SARS-CoV-2%20infection&journal=Nat.%20Commun.&doi=10.1038%2Fs41467-020-17436-6&volume=11&publication_year=2020&author=Vivanti%2CAJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="54."><p class="c-article-references__text" id="ref-CR54">Khalaf, K. et al. SARS-CoV-2: pathogenesis, and advancements in diagnostics and treatment. <i>Front. Immunol.</i> <b>11</b>, 570927 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fimmu.2020.570927" data-track-item_id="10.3389/fimmu.2020.570927" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffimmu.2020.570927" aria-label="Article reference 54" data-doi="10.3389/fimmu.2020.570927">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1Kjur7J" aria-label="CAS reference 54">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33123144" aria-label="PubMed reference 54">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573101" aria-label="PubMed Central reference 54">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 54" href="http://scholar.google.com/scholar_lookup?&title=SARS-CoV-2%3A%20pathogenesis%2C%20and%20advancements%20in%20diagnostics%20and%20treatment&journal=Front.%20Immunol.&doi=10.3389%2Ffimmu.2020.570927&volume=11&publication_year=2020&author=Khalaf%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="55."><p class="c-article-references__text" id="ref-CR55">Morawska, L. & Cao, J. Airborne transmission of SARS-CoV-2: the world should face the reality. <i>Environ. Int.</i> <b>139</b>, 105730 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.envint.2020.105730" data-track-item_id="10.1016/j.envint.2020.105730" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.envint.2020.105730" aria-label="Article reference 55" data-doi="10.1016/j.envint.2020.105730">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXntVOit7Y%3D" aria-label="CAS reference 55">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32294574" aria-label="PubMed reference 55">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151430" aria-label="PubMed Central reference 55">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 55" href="http://scholar.google.com/scholar_lookup?&title=Airborne%20transmission%20of%20SARS-CoV-2%3A%20the%20world%20should%20face%20the%20reality&journal=Environ.%20Int.&doi=10.1016%2Fj.envint.2020.105730&volume=139&publication_year=2020&author=Morawska%2CL&author=Cao%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="56."><p class="c-article-references__text" id="ref-CR56">Bai, Y. et al. Presumed asymptomatic carrier transmission of COVID-19. <i>JAMA</i> <b>323</b>, 1406–1407 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1001/jama.2020.2565" data-track-item_id="10.1001/jama.2020.2565" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1001%2Fjama.2020.2565" aria-label="Article reference 56" data-doi="10.1001/jama.2020.2565">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXnvVOjtLk%3D" aria-label="CAS reference 56">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32083643" aria-label="PubMed reference 56">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042844" aria-label="PubMed Central reference 56">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 56" href="http://scholar.google.com/scholar_lookup?&title=Presumed%20asymptomatic%20carrier%20transmission%20of%20COVID-19&journal=JAMA&doi=10.1001%2Fjama.2020.2565&volume=323&pages=1406-1407&publication_year=2020&author=Bai%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="57."><p class="c-article-references__text" id="ref-CR57">Frampton, D. et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. <i>Lancet Infect. Dis</i>. <b>21</b>, 1246–1256 (2021).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="58."><p class="c-article-references__text" id="ref-CR58">Zhao, S. et al. Inferring the association between the risk of COVID-19 case fatality and N501Y substitution in SARS-CoV-2. <i>Viruses</i> <b>13</b>, 638 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/v13040638" data-track-item_id="10.3390/v13040638" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fv13040638" aria-label="Article reference 58" data-doi="10.3390/v13040638">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhtVanur%2FO" aria-label="CAS reference 58">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33918060" aria-label="PubMed reference 58">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070306" aria-label="PubMed Central reference 58">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 58" href="http://scholar.google.com/scholar_lookup?&title=Inferring%20the%20association%20between%20the%20risk%20of%20COVID-19%20case%20fatality%20and%20N501Y%20substitution%20in%20SARS-CoV-2&journal=Viruses&doi=10.3390%2Fv13040638&volume=13&publication_year=2021&author=Zhao%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="59."><p class="c-article-references__text" id="ref-CR59">Galloway, S. E. et al. Emergence of SARS-CoV-2 B.1.1.7 lineage-United States, December 29, 2020-January 12, 2021. <i>MMWR Morb. Mortal. Wkly. Rep.</i> <b>70</b>, 95–99 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.15585/mmwr.mm7003e2" data-track-item_id="10.15585/mmwr.mm7003e2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.15585%2Fmmwr.mm7003e2" aria-label="Article reference 59" data-doi="10.15585/mmwr.mm7003e2">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXitl2lu7c%3D" aria-label="CAS reference 59">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33476315" aria-label="PubMed reference 59">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821772" aria-label="PubMed Central reference 59">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 59" href="http://scholar.google.com/scholar_lookup?&title=Emergence%20of%20SARS-CoV-2%20B.1.1.7%20lineage-United%20States%2C%20December%2029%2C%202020-January%2012%2C%202021&journal=MMWR%20Morb.%20Mortal.%20Wkly.%20Rep.&doi=10.15585%2Fmmwr.mm7003e2&volume=70&pages=95-99&publication_year=2021&author=Galloway%2CSE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="60."><p class="c-article-references__text" id="ref-CR60">Wang, Q. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. <i>Cell</i> <b>181</b>, 894–904.e9 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cell.2020.03.045" data-track-item_id="10.1016/j.cell.2020.03.045" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cell.2020.03.045" aria-label="Article reference 60" data-doi="10.1016/j.cell.2020.03.045">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXmvFGrur4%3D" aria-label="CAS reference 60">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32275855" aria-label="PubMed reference 60">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144619" aria-label="PubMed Central reference 60">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 60" href="http://scholar.google.com/scholar_lookup?&title=Structural%20and%20functional%20basis%20of%20SARS-CoV-2%20entry%20by%20using%20human%20ACE2&journal=Cell&doi=10.1016%2Fj.cell.2020.03.045&volume=181&pages=894-904.e9&publication_year=2020&author=Wang%2CQ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="61."><p class="c-article-references__text" id="ref-CR61">Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. <i>Cell</i> <b>181</b>, 271–280.e8 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cell.2020.02.052" data-track-item_id="10.1016/j.cell.2020.02.052" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cell.2020.02.052" aria-label="Article reference 61" data-doi="10.1016/j.cell.2020.02.052">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXktl2qtb8%3D" aria-label="CAS reference 61">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32142651" aria-label="PubMed reference 61">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102627" aria-label="PubMed Central reference 61">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 61" href="http://scholar.google.com/scholar_lookup?&title=SARS-CoV-2%20cell%20entry%20depends%20on%20ACE2%20and%20TMPRSS2%20and%20is%20blocked%20by%20a%20clinically%20proven%20protease%20inhibitor&journal=Cell&doi=10.1016%2Fj.cell.2020.02.052&volume=181&pages=271-280.e8&publication_year=2020&author=Hoffmann%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="62."><p class="c-article-references__text" id="ref-CR62">Li, F., Li, W., Farzan, M. & Harrison, S. C. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. <i>Science</i> <b>309</b>, 1864–1868 (2005).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1126/science.1116480" data-track-item_id="10.1126/science.1116480" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1126%2Fscience.1116480" aria-label="Article reference 62" data-doi="10.1126/science.1116480">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXpvFCisLw%3D" aria-label="CAS reference 62">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16166518" aria-label="PubMed reference 62">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 62" href="http://scholar.google.com/scholar_lookup?&title=Structure%20of%20SARS%20coronavirus%20spike%20receptor-binding%20domain%20complexed%20with%20receptor&journal=Science&doi=10.1126%2Fscience.1116480&volume=309&pages=1864-1868&publication_year=2005&author=Li%2CF&author=Li%2CW&author=Farzan%2CM&author=Harrison%2CSC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="63."><p class="c-article-references__text" id="ref-CR63">Zipeto, D., Palmeira, J. D. F., Argañaraz, G. A. & Argañaraz, E. R. ACE2/ADAM17/TMPRSS2 interplay may be the main risk factor for COVID-19. <i>Front. Immunol.</i> <b>11</b>, 576745 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fimmu.2020.576745" data-track-item_id="10.3389/fimmu.2020.576745" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffimmu.2020.576745" aria-label="Article reference 63" data-doi="10.3389/fimmu.2020.576745">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1CntL7L" aria-label="CAS reference 63">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33117379" aria-label="PubMed reference 63">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575774" aria-label="PubMed Central reference 63">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 63" href="http://scholar.google.com/scholar_lookup?&title=ACE2%2FADAM17%2FTMPRSS2%20interplay%20may%20be%20the%20main%20risk%20factor%20for%20COVID-19&journal=Front.%20Immunol.&doi=10.3389%2Ffimmu.2020.576745&volume=11&publication_year=2020&author=Zipeto%2CD&author=Palmeira%2CJDF&author=Arga%C3%B1araz%2CGA&author=Arga%C3%B1araz%2CER"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="64."><p class="c-article-references__text" id="ref-CR64">Smatti, M. K., Al-Sarraj, Y. A., Albagha, O. & Yassine, H. M. Host genetic variants potentially associated with SARS-CoV-2: a multi-population analysis. <i>Front. Genet.</i> <b>11</b>, 578523 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fgene.2020.578523" data-track-item_id="10.3389/fgene.2020.578523" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffgene.2020.578523" aria-label="Article reference 64" data-doi="10.3389/fgene.2020.578523">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1Gjur7K" aria-label="CAS reference 64">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33133166" aria-label="PubMed reference 64">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567011" aria-label="PubMed Central reference 64">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 64" href="http://scholar.google.com/scholar_lookup?&title=Host%20genetic%20variants%20potentially%20associated%20with%20SARS-CoV-2%3A%20a%20multi-population%20analysis&journal=Front.%20Genet.&doi=10.3389%2Ffgene.2020.578523&volume=11&publication_year=2020&author=Smatti%2CMK&author=Al-Sarraj%2CYA&author=Albagha%2CO&author=Yassine%2CHM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="65."><p class="c-article-references__text" id="ref-CR65">Liu, C., von Brunn, A. & Zhu, D. Cyclophilin A and CD147: novel therapeutic targets for the treatment of COVID-19. <i>Med. Drug Discov.</i> <b>7</b>, 100056 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.medidd.2020.100056" data-track-item_id="10.1016/j.medidd.2020.100056" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.medidd.2020.100056" aria-label="Article reference 65" data-doi="10.1016/j.medidd.2020.100056">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32835213" aria-label="PubMed reference 65">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364167" aria-label="PubMed Central reference 65">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 65" href="http://scholar.google.com/scholar_lookup?&title=Cyclophilin%20A%20and%20CD147%3A%20novel%20therapeutic%20targets%20for%20the%20treatment%20of%20COVID-19&journal=Med.%20Drug%20Discov.&doi=10.1016%2Fj.medidd.2020.100056&volume=7&publication_year=2020&author=Liu%2CC&author=Brunn%2CA&author=Zhu%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="66."><p class="c-article-references__text" id="ref-CR66">Wang, S. et al. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. <i>Cell Res.</i> <b>31</b>, 126–140 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41422-020-00460-y" data-track-item_id="10.1038/s41422-020-00460-y" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41422-020-00460-y" aria-label="Article reference 66" data-doi="10.1038/s41422-020-00460-y">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhs1Sjs7s%3D" aria-label="CAS reference 66">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33420426" aria-label="PubMed reference 66">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 66" href="http://scholar.google.com/scholar_lookup?&title=AXL%20is%20a%20candidate%20receptor%20for%20SARS-CoV-2%20that%20promotes%20infection%20of%20pulmonary%20and%20bronchial%20epithelial%20cells&journal=Cell%20Res.&doi=10.1038%2Fs41422-020-00460-y&volume=31&pages=126-140&publication_year=2021&author=Wang%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="67."><p class="c-article-references__text" id="ref-CR67">Ibrahim, I. M., Abdelmalek, D. H., Elshahat, M. E. & Elfiky, A. A. COVID-19 spike-host cell receptor GRP78 binding site prediction. <i>J. Infect.</i> <b>80</b>, 554–562 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jinf.2020.02.026" data-track-item_id="10.1016/j.jinf.2020.02.026" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jinf.2020.02.026" aria-label="Article reference 67" data-doi="10.1016/j.jinf.2020.02.026">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtVant7%2FJ" aria-label="CAS reference 67">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32169481" aria-label="PubMed reference 67">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102553" aria-label="PubMed Central reference 67">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 67" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20spike-host%20cell%20receptor%20GRP78%20binding%20site%20prediction&journal=J.%20Infect.&doi=10.1016%2Fj.jinf.2020.02.026&volume=80&pages=554-562&publication_year=2020&author=Ibrahim%2CIM&author=Abdelmalek%2CDH&author=Elshahat%2CME&author=Elfiky%2CAA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="68."><p class="c-article-references__text" id="ref-CR68">Vankadari, N. & Wilce, J. A. Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. <i>Emerg. Microbes Infect.</i> <b>9</b>, 601–604 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1080/22221751.2020.1739565" data-track-item_id="10.1080/22221751.2020.1739565" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1080%2F22221751.2020.1739565" aria-label="Article reference 68" data-doi="10.1080/22221751.2020.1739565">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXovVWmtLo%3D" aria-label="CAS reference 68">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32178593" aria-label="PubMed reference 68">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103712" aria-label="PubMed Central reference 68">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 68" href="http://scholar.google.com/scholar_lookup?&title=Emerging%20COVID-19%20coronavirus%3A%20glycan%20shield%20and%20structure%20prediction%20of%20spike%20glycoprotein%20and%20its%20interaction%20with%20human%20CD26&journal=Emerg.%20Microbes%20Infect.&doi=10.1080%2F22221751.2020.1739565&volume=9&pages=601-604&publication_year=2020&author=Vankadari%2CN&author=Wilce%2CJA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="69."><p class="c-article-references__text" id="ref-CR69">Daniloski, Z. et al. Identification of required host factors for SARS-CoV-2 infection in human cells. <i>Cell</i> <b>184</b>, 92–105.e16 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cell.2020.10.030" data-track-item_id="10.1016/j.cell.2020.10.030" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cell.2020.10.030" aria-label="Article reference 69" data-doi="10.1016/j.cell.2020.10.030">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit1GqsL3L" aria-label="CAS reference 69">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33147445" aria-label="PubMed reference 69">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 69" href="http://scholar.google.com/scholar_lookup?&title=Identification%20of%20required%20host%20factors%20for%20SARS-CoV-2%20infection%20in%20human%20cells&journal=Cell&doi=10.1016%2Fj.cell.2020.10.030&volume=184&pages=92-105.e16&publication_year=2021&author=Daniloski%2CZ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="70."><p class="c-article-references__text" id="ref-CR70">Latini, A. et al. COVID-19 and genetic variants of protein involved in the SARS-CoV-2 entry into the host cells. <i>Genes</i> <b>11</b>, 1010 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/genes11091010" data-track-item_id="10.3390/genes11091010" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fgenes11091010" aria-label="Article reference 70" data-doi="10.3390/genes11091010">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFKmtrnP" aria-label="CAS reference 70">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565048" aria-label="PubMed Central reference 70">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 70" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20and%20genetic%20variants%20of%20protein%20involved%20in%20the%20SARS-CoV-2%20entry%20into%20the%20host%20cells&journal=Genes&doi=10.3390%2Fgenes11091010&volume=11&publication_year=2020&author=Latini%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="71."><p class="c-article-references__text" id="ref-CR71">Li, Z. L. & Buck, M. Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of spike protein domains S1 and S2. <i>Biophys. J.</i> <b>120</b>, 2828–2837 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.bpj.2021.05.026" data-track-item_id="10.1016/j.bpj.2021.05.026" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.bpj.2021.05.026" aria-label="Article reference 71" data-doi="10.1016/j.bpj.2021.05.026">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhsVKksr%2FK" aria-label="CAS reference 71">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=34087218" aria-label="PubMed reference 71">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169233" aria-label="PubMed Central reference 71">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 71" href="http://scholar.google.com/scholar_lookup?&title=Neuropilin-1%20assists%20SARS-CoV-2%20infection%20by%20stimulating%20the%20separation%20of%20spike%20protein%20domains%20S1%20and%20S2&journal=Biophys.%20J.&doi=10.1016%2Fj.bpj.2021.05.026&volume=120&pages=2828-2837&publication_year=2021&author=Li%2CZL&author=Buck%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="72."><p class="c-article-references__text" id="ref-CR72">Verdecchia, P., Cavallini, C., Spanevello, A. & Angeli, F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. <i>Eur. J. Intern. Med.</i> <b>76</b>, 14–20 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.ejim.2020.04.037" data-track-item_id="10.1016/j.ejim.2020.04.037" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.ejim.2020.04.037" aria-label="Article reference 72" data-doi="10.1016/j.ejim.2020.04.037">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXotVCntLw%3D" aria-label="CAS reference 72">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32336612" aria-label="PubMed reference 72">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167588" aria-label="PubMed Central reference 72">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 72" href="http://scholar.google.com/scholar_lookup?&title=The%20pivotal%20link%20between%20ACE2%20deficiency%20and%20SARS-CoV-2%20infection&journal=Eur.%20J.%20Intern.%20Med.&doi=10.1016%2Fj.ejim.2020.04.037&volume=76&pages=14-20&publication_year=2020&author=Verdecchia%2CP&author=Cavallini%2CC&author=Spanevello%2CA&author=Angeli%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="73."><p class="c-article-references__text" id="ref-CR73">Rodríguez, C. et al. Pulmonary endothelial dysfunction and thrombotic complications in COVID-19 patients. <i>Am. J. Respir. Cell Mol. Biol.</i> <b>64</b>, 407–415 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1165/rcmb.2020-0359PS" data-track-item_id="10.1165/rcmb.2020-0359PS" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1165%2Frcmb.2020-0359PS" aria-label="Article reference 73" data-doi="10.1165/rcmb.2020-0359PS">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 73" href="http://scholar.google.com/scholar_lookup?&title=Pulmonary%20endothelial%20dysfunction%20and%20thrombotic%20complications%20in%20COVID-19%20patients&journal=Am.%20J.%20Respir.%20Cell%20Mol.%20Biol.&doi=10.1165%2Frcmb.2020-0359PS&volume=64&pages=407-415&publication_year=2020&author=Rodr%C3%ADguez%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="74."><p class="c-article-references__text" id="ref-CR74">Vaduganathan, M. et al. Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19. <i>N. Engl. J. Med.</i> <b>382</b>, 1653–1659 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1056/NEJMsr2005760" data-track-item_id="10.1056/NEJMsr2005760" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1056%2FNEJMsr2005760" aria-label="Article reference 74" data-doi="10.1056/NEJMsr2005760">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXot1Klsrs%3D" aria-label="CAS reference 74">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32227760" aria-label="PubMed reference 74">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 74" href="http://scholar.google.com/scholar_lookup?&title=Renin-angiotensin-aldosterone%20system%20inhibitors%20in%20patients%20with%20COVID-19&journal=N.%20Engl.%20J.%20Med.&doi=10.1056%2FNEJMsr2005760&volume=382&pages=1653-1659&publication_year=2020&author=Vaduganathan%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="75."><p class="c-article-references__text" id="ref-CR75">Medina-Enríquez, M. M. et al. ACE2: the molecular doorway to SARS-CoV-2. <i>Cell Biosci.</i> <b>10</b>, 148 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13578-020-00519-8" data-track-item_id="10.1186/s13578-020-00519-8" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13578-020-00519-8" aria-label="Article reference 75" data-doi="10.1186/s13578-020-00519-8">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33380340" aria-label="PubMed reference 75">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772801" aria-label="PubMed Central reference 75">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXkslymtQ%3D%3D" aria-label="CAS reference 75">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 75" href="http://scholar.google.com/scholar_lookup?&title=ACE2%3A%20the%20molecular%20doorway%20to%20SARS-CoV-2&journal=Cell%20Biosci.&doi=10.1186%2Fs13578-020-00519-8&volume=10&publication_year=2020&author=Medina-Enr%C3%ADquez%2CMM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="76."><p class="c-article-references__text" id="ref-CR76">Warner, F. J., Smith, A. I., Hooper, N. M. & Turner, A. J. Angiotensin-converting enzyme-2: a molecular and cellular perspective. <i>Cell Mol. Life Sci.</i> <b>61</b>, 2704–2713 (2004).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00018-004-4240-7" data-track-item_id="10.1007/s00018-004-4240-7" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00018-004-4240-7" aria-label="Article reference 76" data-doi="10.1007/s00018-004-4240-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2cXhtFGit7rI" aria-label="CAS reference 76">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15549171" aria-label="PubMed reference 76">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079784" aria-label="PubMed Central reference 76">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 76" href="http://scholar.google.com/scholar_lookup?&title=Angiotensin-converting%20enzyme-2%3A%20a%20molecular%20and%20cellular%20perspective&journal=Cell%20Mol.%20Life%20Sci.&doi=10.1007%2Fs00018-004-4240-7&volume=61&pages=2704-2713&publication_year=2004&author=Warner%2CFJ&author=Smith%2CAI&author=Hooper%2CNM&author=Turner%2CAJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="77."><p class="c-article-references__text" id="ref-CR77">Bader, M. & Ganten, D. Update on tissue renin-angiotensin systems. <i>J. Mol. Med.</i> <b>86</b>, 615–621 (2008).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00109-008-0336-0" data-track-item_id="10.1007/s00109-008-0336-0" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00109-008-0336-0" aria-label="Article reference 77" data-doi="10.1007/s00109-008-0336-0">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXls1Klt70%3D" aria-label="CAS reference 77">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18414822" aria-label="PubMed reference 77">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 77" href="http://scholar.google.com/scholar_lookup?&title=Update%20on%20tissue%20renin-angiotensin%20systems&journal=J.%20Mol.%20Med.&doi=10.1007%2Fs00109-008-0336-0&volume=86&pages=615-621&publication_year=2008&author=Bader%2CM&author=Ganten%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="78."><p class="c-article-references__text" id="ref-CR78">Donoghue, M. et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. <i>Circ. Res.</i> <b>87</b>, e1–e9 (2000).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1161/01.RES.87.5.e1" data-track-item_id="10.1161/01.RES.87.5.e1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1161%2F01.RES.87.5.e1" aria-label="Article reference 78" data-doi="10.1161/01.RES.87.5.e1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3MXhslOisr8%3D" aria-label="CAS reference 78">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10969042" aria-label="PubMed reference 78">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 78" href="http://scholar.google.com/scholar_lookup?&title=A%20novel%20angiotensin-converting%20enzyme-related%20carboxypeptidase%20%28ACE2%29%20converts%20angiotensin%20I%20to%20angiotensin%201-9&journal=Circ.%20Res.&doi=10.1161%2F01.RES.87.5.e1&volume=87&pages=e1-e9&publication_year=2000&author=Donoghue%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="79."><p class="c-article-references__text" id="ref-CR79">Patel, V. B., Zhong, J. C., Grant, M. B. & Oudit, G. Y. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. <i>Circ. Res.</i> <b>118</b>, 1313–1326 (2016).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1161/CIRCRESAHA.116.307708" data-track-item_id="10.1161/CIRCRESAHA.116.307708" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1161%2FCIRCRESAHA.116.307708" aria-label="Article reference 79" data-doi="10.1161/CIRCRESAHA.116.307708">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XmtVaht7s%3D" aria-label="CAS reference 79">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27081112" aria-label="PubMed reference 79">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939482" aria-label="PubMed Central reference 79">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 79" href="http://scholar.google.com/scholar_lookup?&title=Role%20of%20the%20ACE2%2Fangiotensin%201-7%20axis%20of%20the%20renin-angiotensin%20system%20in%20heart%20failure&journal=Circ.%20Res.&doi=10.1161%2FCIRCRESAHA.116.307708&volume=118&pages=1313-1326&publication_year=2016&author=Patel%2CVB&author=Zhong%2CJC&author=Grant%2CMB&author=Oudit%2CGY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="80."><p class="c-article-references__text" id="ref-CR80">Sieńko, J. et al. COVID-19: the influence of ACE genotype and ACE-I and ARBs on the course of SARS-CoV-2 infection in elderly patients. <i>Clin. Inter. Aging</i> <b>15</b>, 1231–1240 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.2147/CIA.S261516" data-track-item_id="10.2147/CIA.S261516" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.2147%2FCIA.S261516" aria-label="Article reference 80" data-doi="10.2147/CIA.S261516">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 80" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%3A%20the%20influence%20of%20ACE%20genotype%20and%20ACE-I%20and%20ARBs%20on%20the%20course%20of%20SARS-CoV-2%20infection%20in%20elderly%20patients&journal=Clin.%20Inter.%20Aging&doi=10.2147%2FCIA.S261516&volume=15&pages=1231-1240&publication_year=2020&author=Sie%C5%84ko%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="81."><p class="c-article-references__text" id="ref-CR81">Hamming, I. et al. The emerging role of ACE2 in physiology and disease. <i>J. Pathol.</i> <b>212</b>, 1–11 (2007).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/path.2162" data-track-item_id="10.1002/path.2162" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fpath.2162" aria-label="Article reference 81" data-doi="10.1002/path.2162">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXmt1eisL4%3D" aria-label="CAS reference 81">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17464936" aria-label="PubMed reference 81">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167724" aria-label="PubMed Central reference 81">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 81" href="http://scholar.google.com/scholar_lookup?&title=The%20emerging%20role%20of%20ACE2%20in%20physiology%20and%20disease&journal=J.%20Pathol.&doi=10.1002%2Fpath.2162&volume=212&pages=1-11&publication_year=2007&author=Hamming%2CI"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="82."><p class="c-article-references__text" id="ref-CR82">Haitao, T. et al. COVID-19 and sex differences: mechanisms and biomarkers. <i>Mayo Clin. Proc.</i> <b>95</b>, 2189–2203 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.mayocp.2020.07.024" data-track-item_id="10.1016/j.mayocp.2020.07.024" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.mayocp.2020.07.024" aria-label="Article reference 82" data-doi="10.1016/j.mayocp.2020.07.024">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsleksLjL" aria-label="CAS reference 82">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33012349" aria-label="PubMed reference 82">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 82" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20and%20sex%20differences%3A%20mechanisms%20and%20biomarkers&journal=Mayo%20Clin.%20Proc.&doi=10.1016%2Fj.mayocp.2020.07.024&volume=95&pages=2189-2203&publication_year=2020&author=Haitao%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="83."><p class="c-article-references__text" id="ref-CR83">Burrell, L. M., Johnston, C. I., Tikellis, C. & Cooper, M. E. ACE2, a new regulator of the renin-angiotensin system. <i>Trends Endocrinol. Metab.</i> <b>15</b>, 166–169 (2004).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.tem.2004.03.001" data-track-item_id="10.1016/j.tem.2004.03.001" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.tem.2004.03.001" aria-label="Article reference 83" data-doi="10.1016/j.tem.2004.03.001">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2cXjsVeguro%3D" aria-label="CAS reference 83">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15109615" aria-label="PubMed reference 83">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128798" aria-label="PubMed Central reference 83">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 83" href="http://scholar.google.com/scholar_lookup?&title=ACE2%2C%20a%20new%20regulator%20of%20the%20renin-angiotensin%20system&journal=Trends%20Endocrinol.%20Metab.&doi=10.1016%2Fj.tem.2004.03.001&volume=15&pages=166-169&publication_year=2004&author=Burrell%2CLM&author=Johnston%2CCI&author=Tikellis%2CC&author=Cooper%2CME"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="84."><p class="c-article-references__text" id="ref-CR84">Vickers, C. et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. <i>J. Biol. Chem.</i> <b>277</b>, 14838–14843 (2002).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1074/jbc.M200581200" data-track-item_id="10.1074/jbc.M200581200" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1074%2Fjbc.M200581200" aria-label="Article reference 84" data-doi="10.1074/jbc.M200581200">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD38XjslSgsbo%3D" aria-label="CAS reference 84">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11815627" aria-label="PubMed reference 84">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 84" href="http://scholar.google.com/scholar_lookup?&title=Hydrolysis%20of%20biological%20peptides%20by%20human%20angiotensin-converting%20enzyme-related%20carboxypeptidase&journal=J.%20Biol.%20Chem.&doi=10.1074%2Fjbc.M200581200&volume=277&pages=14838-14843&publication_year=2002&author=Vickers%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="85."><p class="c-article-references__text" id="ref-CR85">Cheng, H., Wang, Y. & Wang, G. Q. Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19. <i>J. Med. Virol.</i> <b>92</b>, 726–730 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/jmv.25785" data-track-item_id="10.1002/jmv.25785" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fjmv.25785" aria-label="Article reference 85" data-doi="10.1002/jmv.25785">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXnsVWqtbs%3D" aria-label="CAS reference 85">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32221983" aria-label="PubMed reference 85">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317908" aria-label="PubMed Central reference 85">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 85" href="http://scholar.google.com/scholar_lookup?&title=Organ-protective%20effect%20of%20angiotensin-converting%20enzyme%202%20and%20its%20effect%20on%20the%20prognosis%20of%20COVID-19&journal=J.%20Med.%20Virol.&doi=10.1002%2Fjmv.25785&volume=92&pages=726-730&publication_year=2020&author=Cheng%2CH&author=Wang%2CY&author=Wang%2CGQ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="86."><p class="c-article-references__text" id="ref-CR86">Yamamoto, N. et al. SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype. <i>Gene</i> <b>758</b>, 144944 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.gene.2020.144944" data-track-item_id="10.1016/j.gene.2020.144944" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.gene.2020.144944" aria-label="Article reference 86" data-doi="10.1016/j.gene.2020.144944">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVWqurzK" aria-label="CAS reference 86">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32628976" aria-label="PubMed reference 86">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833925" aria-label="PubMed Central reference 86">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 86" href="http://scholar.google.com/scholar_lookup?&title=SARS-CoV-2%20infections%20and%20COVID-19%20mortalities%20strongly%20correlate%20with%20ACE1%20I%2FD%20genotype&journal=Gene&doi=10.1016%2Fj.gene.2020.144944&volume=758&publication_year=2020&author=Yamamoto%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="87."><p class="c-article-references__text" id="ref-CR87">Arnold, R. H. COVID-19-does this disease kill due to imbalance of the renin angiotensin system (RAS) caused by genetic and gender differences in the response to viral ACE2 attack? <i>Heart Lung Circ.</i> <b>29</b>, 964–972 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.hlc.2020.05.004" data-track-item_id="10.1016/j.hlc.2020.05.004" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.hlc.2020.05.004" aria-label="Article reference 87" data-doi="10.1016/j.hlc.2020.05.004">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32564908" aria-label="PubMed reference 87">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247492" aria-label="PubMed Central reference 87">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 87" href="http://scholar.google.com/scholar_lookup?&title=COVID-19-does%20this%20disease%20kill%20due%20to%20imbalance%20of%20the%20renin%20angiotensin%20system%20%28RAS%29%20caused%20by%20genetic%20and%20gender%20differences%20in%20the%20response%20to%20viral%20ACE2%20attack%3F&journal=Heart%20Lung%20Circ.&doi=10.1016%2Fj.hlc.2020.05.004&volume=29&pages=964-972&publication_year=2020&author=Arnold%2CRH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="88."><p class="c-article-references__text" id="ref-CR88">Mangalmurti, N. & Hunter, C. A. Cytokine storms: understanding COVID-19. <i>Immunity</i> <b>53</b>, 19–25 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.immuni.2020.06.017" data-track-item_id="10.1016/j.immuni.2020.06.017" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.immuni.2020.06.017" aria-label="Article reference 88" data-doi="10.1016/j.immuni.2020.06.017">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXht1yls7bF" aria-label="CAS reference 88">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32610079" aria-label="PubMed reference 88">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321048" aria-label="PubMed Central reference 88">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 88" href="http://scholar.google.com/scholar_lookup?&title=Cytokine%20storms%3A%20understanding%20COVID-19&journal=Immunity&doi=10.1016%2Fj.immuni.2020.06.017&volume=53&pages=19-25&publication_year=2020&author=Mangalmurti%2CN&author=Hunter%2CCA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="89."><p class="c-article-references__text" id="ref-CR89">Yang, L. et al. COVID-19: immunopathogenesis and immunotherapeutics. <i>Signal Transduct. Target. Ther.</i> <b>5</b>, 128 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41392-020-00243-2" data-track-item_id="10.1038/s41392-020-00243-2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41392-020-00243-2" aria-label="Article reference 89" data-doi="10.1038/s41392-020-00243-2">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVGlur3F" aria-label="CAS reference 89">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32712629" aria-label="PubMed reference 89">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381863" aria-label="PubMed Central reference 89">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 89" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%3A%20immunopathogenesis%20and%20immunotherapeutics&journal=Signal%20Transduct.%20Target.%20Ther.&doi=10.1038%2Fs41392-020-00243-2&volume=5&publication_year=2020&author=Yang%2CL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="90."><p class="c-article-references__text" id="ref-CR90">Molaei, S., Dadkhah, M., Asghariazar, V., Karami, C. & Safarzadeh, E. The immune response and immune evasion characteristics in SARS-CoV, MERS-CoV, and SARS-CoV-2: vaccine design strategies. <i>Int. Immunopharmacol.</i> <b>92</b>, 107051 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.intimp.2020.107051" data-track-item_id="10.1016/j.intimp.2020.107051" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.intimp.2020.107051" aria-label="Article reference 90" data-doi="10.1016/j.intimp.2020.107051">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhtVGnt70%3D" aria-label="CAS reference 90">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33429331" aria-label="PubMed reference 90">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 90" href="http://scholar.google.com/scholar_lookup?&title=The%20immune%20response%20and%20immune%20evasion%20characteristics%20in%20SARS-CoV%2C%20MERS-CoV%2C%20and%20SARS-CoV-2%3A%20vaccine%20design%20strategies&journal=Int.%20Immunopharmacol.&doi=10.1016%2Fj.intimp.2020.107051&volume=92&publication_year=2021&author=Molaei%2CS&author=Dadkhah%2CM&author=Asghariazar%2CV&author=Karami%2CC&author=Safarzadeh%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="91."><p class="c-article-references__text" id="ref-CR91">Mohamed Khosroshahi, L., Rokni, M., Mokhtari, T. & Noorbakhsh, F. Immunology, immunopathogenesis and immunotherapeutics of COVID-19; an overview. <i>Int. Immunopharmacol.</i> <b>93</b>, 107364 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.intimp.2020.107364" data-track-item_id="10.1016/j.intimp.2020.107364" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.intimp.2020.107364" aria-label="Article reference 91" data-doi="10.1016/j.intimp.2020.107364">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXitFWht7c%3D" aria-label="CAS reference 91">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33486333" aria-label="PubMed reference 91">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784533" aria-label="PubMed Central reference 91">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 91" href="http://scholar.google.com/scholar_lookup?&title=Immunology%2C%20immunopathogenesis%20and%20immunotherapeutics%20of%20COVID-19%3B%20an%20overview&journal=Int.%20Immunopharmacol.&doi=10.1016%2Fj.intimp.2020.107364&volume=93&publication_year=2021&author=Mohamed%20Khosroshahi%2CL&author=Rokni%2CM&author=Mokhtari%2CT&author=Noorbakhsh%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="92."><p class="c-article-references__text" id="ref-CR92">Catanzaro, M. et al. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. <i>Signal Transduct. Target. Ther.</i> <b>5</b>, 84 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41392-020-0191-1" data-track-item_id="10.1038/s41392-020-0191-1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41392-020-0191-1" aria-label="Article reference 92" data-doi="10.1038/s41392-020-0191-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtVOjs7zL" aria-label="CAS reference 92">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32467561" aria-label="PubMed reference 92">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255975" aria-label="PubMed Central reference 92">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 92" href="http://scholar.google.com/scholar_lookup?&title=Immune%20response%20in%20COVID-19%3A%20addressing%20a%20pharmacological%20challenge%20by%20targeting%20pathways%20triggered%20by%20SARS-CoV-2&journal=Signal%20Transduct.%20Target.%20Ther.&doi=10.1038%2Fs41392-020-0191-1&volume=5&publication_year=2020&author=Catanzaro%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="93."><p class="c-article-references__text" id="ref-CR93">Ebrahimi, N. et al. Recent findings on the coronavirus disease 2019 (COVID-19); immunopathogenesis and immunotherapeutics. <i>Int. Immunopharmacol.</i> <b>89</b>, 107082 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.intimp.2020.107082" data-track-item_id="10.1016/j.intimp.2020.107082" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.intimp.2020.107082" aria-label="Article reference 93" data-doi="10.1016/j.intimp.2020.107082">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitFeqs7bM" aria-label="CAS reference 93">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33068865" aria-label="PubMed reference 93">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547582" aria-label="PubMed Central reference 93">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 93" href="http://scholar.google.com/scholar_lookup?&title=Recent%20findings%20on%20the%20coronavirus%20disease%202019%20%28COVID-19%29%3B%20immunopathogenesis%20and%20immunotherapeutics&journal=Int.%20Immunopharmacol.&doi=10.1016%2Fj.intimp.2020.107082&volume=89&publication_year=2020&author=Ebrahimi%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="94."><p class="c-article-references__text" id="ref-CR94">Kumar, S., Nyodu, R., Maurya, V. K. & Saxena, S. K. in <i>Coronavirus Disease 2019 (COVID-19): Epidemiology, Pathogenesis, Diagnosis, and Therapeutics</i> (ed. Saxena, S. K.) Ch. 5 (Springer Singapore, 2020).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="95."><p class="c-article-references__text" id="ref-CR95">Schurr, T. G. Host genetic factors and susceptibility to SARS-CoV-2 infection. <i>Am. J. Hum. Biol.</i> <b>32</b>, e23497 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/ajhb.23497" data-track-item_id="10.1002/ajhb.23497" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fajhb.23497" aria-label="Article reference 95" data-doi="10.1002/ajhb.23497">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32876373" aria-label="PubMed reference 95">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 95" href="http://scholar.google.com/scholar_lookup?&title=Host%20genetic%20factors%20and%20susceptibility%20to%20SARS-CoV-2%20infection&journal=Am.%20J.%20Hum.%20Biol.&doi=10.1002%2Fajhb.23497&volume=32&publication_year=2020&author=Schurr%2CTG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="96."><p class="c-article-references__text" id="ref-CR96">Azkur, A. K. et al. Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19. <i>Allergy</i> <b>75</b>, 1564–1581 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/all.14364" data-track-item_id="10.1111/all.14364" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fall.14364" aria-label="Article reference 96" data-doi="10.1111/all.14364">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtlOhtbzN" aria-label="CAS reference 96">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32396996" aria-label="PubMed reference 96">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 96" href="http://scholar.google.com/scholar_lookup?&title=Immune%20response%20to%20SARS-CoV-2%20and%20mechanisms%20of%20immunopathological%20changes%20in%20COVID-19&journal=Allergy&doi=10.1111%2Fall.14364&volume=75&pages=1564-1581&publication_year=2020&author=Azkur%2CAK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="97."><p class="c-article-references__text" id="ref-CR97">Dhama, K. et al. An update on SARS-CoV-2/COVID-19 with particular reference to its clinical pathology, pathogenesis, immunopathology and mitigation strategies. <i>Travel Med. Infect. Dis.</i> <b>37</b>, 101755 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.tmaid.2020.101755" data-track-item_id="10.1016/j.tmaid.2020.101755" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.tmaid.2020.101755" aria-label="Article reference 97" data-doi="10.1016/j.tmaid.2020.101755">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32479816" aria-label="PubMed reference 97">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260597" aria-label="PubMed Central reference 97">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 97" href="http://scholar.google.com/scholar_lookup?&title=An%20update%20on%20SARS-CoV-2%2FCOVID-19%20with%20particular%20reference%20to%20its%20clinical%20pathology%2C%20pathogenesis%2C%20immunopathology%20and%20mitigation%20strategies&journal=Travel%20Med.%20Infect.%20Dis.&doi=10.1016%2Fj.tmaid.2020.101755&volume=37&publication_year=2020&author=Dhama%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="98."><p class="c-article-references__text" id="ref-CR98">Ramos-Lopez, O. et al. Exploring host genetic polymorphisms involved in SARS-CoV infection outcomes: implications for personalized medicine in COVID-19. <i>Int. J. Genomics</i> <b>2020</b>, 6901217 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1155/2020/6901217" data-track-item_id="10.1155/2020/6901217" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1155%2F2020%2F6901217" aria-label="Article reference 98" data-doi="10.1155/2020/6901217">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33110916" aria-label="PubMed reference 98">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582067" aria-label="PubMed Central reference 98">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitlSgsb3K" aria-label="CAS reference 98">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 98" href="http://scholar.google.com/scholar_lookup?&title=Exploring%20host%20genetic%20polymorphisms%20involved%20in%20SARS-CoV%20infection%20outcomes%3A%20implications%20for%20personalized%20medicine%20in%20COVID-19&journal=Int.%20J.%20Genomics&doi=10.1155%2F2020%2F6901217&volume=2020&publication_year=2020&author=Ramos-Lopez%2CO"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="99."><p class="c-article-references__text" id="ref-CR99">Syed, F. et al. Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19. <i>J. Infect. Dis.</i> <b>224</b>, 60–69 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/infdis/jiab167" data-track-item_id="10.1093/infdis/jiab167" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Finfdis%2Fjiab167" aria-label="Article reference 99" data-doi="10.1093/infdis/jiab167">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhs1WjsbrE" aria-label="CAS reference 99">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33885811" aria-label="PubMed reference 99">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083685" aria-label="PubMed Central reference 99">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 99" href="http://scholar.google.com/scholar_lookup?&title=Excessive%20matrix%20metalloproteinase-1%20and%20hyperactivation%20of%20endothelial%20cells%20occurred%20in%20COVID-19%20patients%20and%20were%20associated%20with%20the%20severity%20of%20COVID-19&journal=J.%20Infect.%20Dis.&doi=10.1093%2Finfdis%2Fjiab167&volume=224&pages=60-69&publication_year=2021&author=Syed%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="100."><p class="c-article-references__text" id="ref-CR100">von der Thüsen, J. & van der Eerden, M. Histopathology and genetic susceptibility in COVID-19 pneumonia. <i>Eur. J. Clin. Invest.</i> <b>50</b>, e13259 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32353898" aria-label="PubMed reference 100">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 100" href="http://scholar.google.com/scholar_lookup?&title=Histopathology%20and%20genetic%20susceptibility%20in%20COVID-19%20pneumonia&journal=Eur.%20J.%20Clin.%20Invest.&volume=50&publication_year=2020&author=Th%C3%BCsen%2CJ&author=Eerden%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="101."><p class="c-article-references__text" id="ref-CR101">Gebhard, C., Regitz-Zagrosek, V., Neuhauser, H. K., Morgan, R. & Klein, S. L. Impact of sex and gender on COVID-19 outcomes in Europe. <i>Biol. Sex Differ.</i> <b>11</b>, 29 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13293-020-00304-9" data-track-item_id="10.1186/s13293-020-00304-9" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13293-020-00304-9" aria-label="Article reference 101" data-doi="10.1186/s13293-020-00304-9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtVGnurvJ" aria-label="CAS reference 101">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32450906" aria-label="PubMed reference 101">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247289" aria-label="PubMed Central reference 101">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 101" href="http://scholar.google.com/scholar_lookup?&title=Impact%20of%20sex%20and%20gender%20on%20COVID-19%20outcomes%20in%20Europe&journal=Biol.%20Sex%20Differ.&doi=10.1186%2Fs13293-020-00304-9&volume=11&publication_year=2020&author=Gebhard%2CC&author=Regitz-Zagrosek%2CV&author=Neuhauser%2CHK&author=Morgan%2CR&author=Klein%2CSL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="102."><p class="c-article-references__text" id="ref-CR102">Maiti, A. K. The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection. <i>Immunogenetics</i> <b>72</b>, 387–391 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00251-020-01174-6" data-track-item_id="10.1007/s00251-020-01174-6" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00251-020-01174-6" aria-label="Article reference 102" data-doi="10.1007/s00251-020-01174-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsFaju7vK" aria-label="CAS reference 102">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32737579" aria-label="PubMed reference 102">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394703" aria-label="PubMed Central reference 102">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 102" href="http://scholar.google.com/scholar_lookup?&title=The%20African-American%20population%20with%20a%20low%20allele%20frequency%20of%20SNP%20rs1990760%20%28T%20allele%29%20in%20IFIH1%20predicts%20less%20IFN-beta%20expression%20and%20potential%20vulnerability%20to%20COVID-19%20infection&journal=Immunogenetics&doi=10.1007%2Fs00251-020-01174-6&volume=72&pages=387-391&publication_year=2020&author=Maiti%2CAK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="103."><p class="c-article-references__text" id="ref-CR103">Molineros, J. E. et al. Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production. <i>PLoS Genet.</i> <b>9</b>, e1003222 (2013).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1371/journal.pgen.1003222" data-track-item_id="10.1371/journal.pgen.1003222" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1371%2Fjournal.pgen.1003222" aria-label="Article reference 103" data-doi="10.1371/journal.pgen.1003222">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXkt1Wltrw%3D" aria-label="CAS reference 103">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23441136" aria-label="PubMed reference 103">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3575474" aria-label="PubMed Central reference 103">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 103" href="http://scholar.google.com/scholar_lookup?&title=Admixture%20mapping%20in%20lupus%20identifies%20multiple%20functional%20variants%20within%20IFIH1%20associated%20with%20apoptosis%2C%20inflammation%2C%20and%20autoantibody%20production&journal=PLoS%20Genet.&doi=10.1371%2Fjournal.pgen.1003222&volume=9&publication_year=2013&author=Molineros%2CJE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="104."><p class="c-article-references__text" id="ref-CR104">Ellinghaus, D. et al. Genomewide association study of severe COVID-19 with respiratory failure. <i>N. Engl. J. Med.</i> <b>383</b>, 1522–1534 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1056/NEJMoa2020283" data-track-item_id="10.1056/NEJMoa2020283" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1056%2FNEJMoa2020283" aria-label="Article reference 104" data-doi="10.1056/NEJMoa2020283">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitFWmsLbF" aria-label="CAS reference 104">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32558485" aria-label="PubMed reference 104">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 104" href="http://scholar.google.com/scholar_lookup?&title=Genomewide%20association%20study%20of%20severe%20COVID-19%20with%20respiratory%20failure&journal=N.%20Engl.%20J.%20Med.&doi=10.1056%2FNEJMoa2020283&volume=383&pages=1522-1534&publication_year=2020&author=Ellinghaus%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="105."><p class="c-article-references__text" id="ref-CR105">Ellinghaus, D. et al. The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis. Preprint at <a href="https://www.medrxiv.org/content/early/2020/06/02/2020.05.31.20114991" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://www.medrxiv.org/content/early/2020/06/02/2020.05.31.20114991">https://www.medrxiv.org/content/early/2020/06/02/2020.05.31.20114991</a> (2020).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="106."><p class="c-article-references__text" id="ref-CR106">Wang, F. et al. Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility. <i>Cell Discov.</i> <b>6</b>, 83 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41421-020-00231-4" data-track-item_id="10.1038/s41421-020-00231-4" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41421-020-00231-4" aria-label="Article reference 106" data-doi="10.1038/s41421-020-00231-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit12ktLfP" aria-label="CAS reference 106">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33298875" aria-label="PubMed reference 106">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653987" aria-label="PubMed Central reference 106">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 106" href="http://scholar.google.com/scholar_lookup?&title=Initial%20whole-genome%20sequencing%20and%20analysis%20of%20the%20host%20genetic%20contribution%20to%20COVID-19%20severity%20and%20susceptibility&journal=Cell%20Discov.&doi=10.1038%2Fs41421-020-00231-4&volume=6&publication_year=2020&author=Wang%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="107."><p class="c-article-references__text" id="ref-CR107">Zeberg, H. & Pääbo, S. The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. <i>Nature</i> <b>587</b>, 610–612 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41586-020-2818-3" data-track-item_id="10.1038/s41586-020-2818-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41586-020-2818-3" aria-label="Article reference 107" data-doi="10.1038/s41586-020-2818-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit1ersr3I" aria-label="CAS reference 107">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32998156" aria-label="PubMed reference 107">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 107" href="http://scholar.google.com/scholar_lookup?&title=The%20major%20genetic%20risk%20factor%20for%20severe%20COVID-19%20is%20inherited%20from%20Neanderthals&journal=Nature&doi=10.1038%2Fs41586-020-2818-3&volume=587&pages=610-612&publication_year=2020&author=Zeberg%2CH&author=P%C3%A4%C3%A4bo%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="108."><p class="c-article-references__text" id="ref-CR108">Nelson, R. Risk variant for severe COVID-19 inherited from Neanderthals. <i>Am. J. Med. Genet. A</i> <b>182</b>, 2203–2204 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/ajmg.a.61247" data-track-item_id="10.1002/ajmg.a.61247" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fajmg.a.61247" aria-label="Article reference 108" data-doi="10.1002/ajmg.a.61247">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhvVGit73O" aria-label="CAS reference 108">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 108" href="http://scholar.google.com/scholar_lookup?&title=Risk%20variant%20for%20severe%20COVID-19%20inherited%20from%20Neanderthals&journal=Am.%20J.%20Med.%20Genet.%20A&doi=10.1002%2Fajmg.a.61247&volume=182&pages=2203-2204&publication_year=2020&author=Nelson%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="109."><p class="c-article-references__text" id="ref-CR109">Kwok, A. J., Mentzer, A. & Knight, J. C. Host genetics and infectious disease: new tools, insights and translational opportunities. <i>Nat. Rev. Genet.</i> <b>22</b>, 137–153 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41576-020-00297-6" data-track-item_id="10.1038/s41576-020-00297-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41576-020-00297-6" aria-label="Article reference 109" data-doi="10.1038/s41576-020-00297-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisV2ntL3I" aria-label="CAS reference 109">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33277640" aria-label="PubMed reference 109">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 109" href="http://scholar.google.com/scholar_lookup?&title=Host%20genetics%20and%20infectious%20disease%3A%20new%20tools%2C%20insights%20and%20translational%20opportunities&journal=Nat.%20Rev.%20Genet.&doi=10.1038%2Fs41576-020-00297-6&volume=22&pages=137-153&publication_year=2021&author=Kwok%2CAJ&author=Mentzer%2CA&author=Knight%2CJC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="110."><p class="c-article-references__text" id="ref-CR110">Patel, P., Hiam, L., Sowemimo, A., Devakumar, D. & McKee, M. Ethnicity and covid-19. <i>BMJ</i> <b>369</b>, m2282 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1136/bmj.m2282" data-track-item_id="10.1136/bmj.m2282" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1136%2Fbmj.m2282" aria-label="Article reference 110" data-doi="10.1136/bmj.m2282">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32527732" aria-label="PubMed reference 110">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 110" href="http://scholar.google.com/scholar_lookup?&title=Ethnicity%20and%20covid-19&journal=BMJ&doi=10.1136%2Fbmj.m2282&volume=369&publication_year=2020&author=Patel%2CP&author=Hiam%2CL&author=Sowemimo%2CA&author=Devakumar%2CD&author=McKee%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="111."><p class="c-article-references__text" id="ref-CR111">Sornette, D., Mearns, E., Schatz, M., Wu, K. & Darcet, D. Interpreting, analysing and modelling COVID-19 mortality data. <i>Nonlinear Dyn.</i> <b>101</b>, 1751–1776 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s11071-020-05966-z" data-track-item_id="10.1007/s11071-020-05966-z" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s11071-020-05966-z" aria-label="Article reference 111" data-doi="10.1007/s11071-020-05966-z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33020681" aria-label="PubMed reference 111">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527427" aria-label="PubMed Central reference 111">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 111" href="http://scholar.google.com/scholar_lookup?&title=Interpreting%2C%20analysing%20and%20modelling%20COVID-19%20mortality%20data&journal=Nonlinear%20Dyn.&doi=10.1007%2Fs11071-020-05966-z&volume=101&pages=1751-1776&publication_year=2020&author=Sornette%2CD&author=Mearns%2CE&author=Schatz%2CM&author=Wu%2CK&author=Darcet%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="112."><p class="c-article-references__text" id="ref-CR112">Williamson, E. J. et al. Factors associated with COVID-19-related death using OpenSAFELY. <i>Nature</i> <b>584</b>, 430–436 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41586-020-2521-4" data-track-item_id="10.1038/s41586-020-2521-4" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41586-020-2521-4" aria-label="Article reference 112" data-doi="10.1038/s41586-020-2521-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsFegtbzK" aria-label="CAS reference 112">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32640463" aria-label="PubMed reference 112">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611074" aria-label="PubMed Central reference 112">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 112" href="http://scholar.google.com/scholar_lookup?&title=Factors%20associated%20with%20COVID-19-related%20death%20using%20OpenSAFELY&journal=Nature&doi=10.1038%2Fs41586-020-2521-4&volume=584&pages=430-436&publication_year=2020&author=Williamson%2CEJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="113."><p class="c-article-references__text" id="ref-CR113">Rentsch, C. T. et al. Patterns of COVID-19 testing and mortality by race and ethnicity among United States veterans: a nationwide cohort study. <i>PLoS Med.</i> <b>17</b>, e1003379 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1371/journal.pmed.1003379" data-track-item_id="10.1371/journal.pmed.1003379" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1371%2Fjournal.pmed.1003379" aria-label="Article reference 113" data-doi="10.1371/journal.pmed.1003379">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitVCgu7jJ" aria-label="CAS reference 113">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32960880" aria-label="PubMed reference 113">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508372" aria-label="PubMed Central reference 113">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 113" href="http://scholar.google.com/scholar_lookup?&title=Patterns%20of%20COVID-19%20testing%20and%20mortality%20by%20race%20and%20ethnicity%20among%20United%20States%20veterans%3A%20a%20nationwide%20cohort%20study&journal=PLoS%20Med.&doi=10.1371%2Fjournal.pmed.1003379&volume=17&publication_year=2020&author=Rentsch%2CCT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="114."><p class="c-article-references__text" id="ref-CR114">Webb Hooper, M., Nápoles, A. M. & Pérez-Stable, E. J. COVID-19 and racial/ethnic disparities. <i>JAMA</i> <b>323</b>, 2466–2467 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1001/jama.2020.8598" data-track-item_id="10.1001/jama.2020.8598" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1001%2Fjama.2020.8598" aria-label="Article reference 114" data-doi="10.1001/jama.2020.8598">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32391864" aria-label="PubMed reference 114">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtlSnt7nP" aria-label="CAS reference 114">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 114" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20and%20racial%2Fethnic%20disparities&journal=JAMA&doi=10.1001%2Fjama.2020.8598&volume=323&pages=2466-2467&publication_year=2020&author=Webb%20Hooper%2CM&author=N%C3%A1poles%2CAM&author=P%C3%A9rez-Stable%2CEJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="115."><p class="c-article-references__text" id="ref-CR115">Lorente, L. et al. HLA genetic polymorphisms and prognosis of patients with COVID-19. <i>Med. Intens.</i> <b>45</b>, 96–103 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.medin.2020.08.004" data-track-item_id="10.1016/j.medin.2020.08.004" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.medin.2020.08.004" aria-label="Article reference 115" data-doi="10.1016/j.medin.2020.08.004">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DC%2BB3s%2FkslSrtA%3D%3D" aria-label="CAS reference 115">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 115" href="http://scholar.google.com/scholar_lookup?&title=HLA%20genetic%20polymorphisms%20and%20prognosis%20of%20patients%20with%20COVID-19&journal=Med.%20Intens.&doi=10.1016%2Fj.medin.2020.08.004&volume=45&pages=96-103&publication_year=2021&author=Lorente%2CL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="116."><p class="c-article-references__text" id="ref-CR116">La Porta, C. A. M. & Zapperi, S. Estimating the binding of SARS-CoV-2 peptides to HLA class I in human subpopulations using artificial neural networks. <i>Cell Syst.</i> <b>11</b>, 412–417 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cels.2020.08.011" data-track-item_id="10.1016/j.cels.2020.08.011" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cels.2020.08.011" aria-label="Article reference 116" data-doi="10.1016/j.cels.2020.08.011">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitF2jtbfF" aria-label="CAS reference 116">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32916095" aria-label="PubMed reference 116">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488596" aria-label="PubMed Central reference 116">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 116" href="http://scholar.google.com/scholar_lookup?&title=Estimating%20the%20binding%20of%20SARS-CoV-2%20peptides%20to%20HLA%20class%20I%20in%20human%20subpopulations%20using%20artificial%20neural%20networks&journal=Cell%20Syst.&doi=10.1016%2Fj.cels.2020.08.011&volume=11&pages=412-417&publication_year=2020&author=La%20Porta%2CCAM&author=Zapperi%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="117."><p class="c-article-references__text" id="ref-CR117">Tomita, Y., Ikeda, T., Sato, R. & Sakagami, T. Association between HLA gene polymorphisms and mortality of COVID-19: an in silico analysis. <i>Immun. Inflamm. Dis.</i> <b>8</b>, 684–694 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/iid3.358" data-track-item_id="10.1002/iid3.358" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fiid3.358" aria-label="Article reference 117" data-doi="10.1002/iid3.358">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit1Ontr%2FM" aria-label="CAS reference 117">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33047883" aria-label="PubMed reference 117">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654404" aria-label="PubMed Central reference 117">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 117" href="http://scholar.google.com/scholar_lookup?&title=Association%20between%20HLA%20gene%20polymorphisms%20and%20mortality%20of%20COVID-19%3A%20an%20in%20silico%20analysis&journal=Immun.%20Inflamm.%20Dis.&doi=10.1002%2Fiid3.358&volume=8&pages=684-694&publication_year=2020&author=Tomita%2CY&author=Ikeda%2CT&author=Sato%2CR&author=Sakagami%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="118."><p class="c-article-references__text" id="ref-CR118">Yung, Y. L. et al. Association of HLA-B22 serotype with SARS-CoV-2 susceptibility in Hong Kong Chinese patients. <i>HLA</i> <b>97</b>, 127–132 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/tan.14135" data-track-item_id="10.1111/tan.14135" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Ftan.14135" aria-label="Article reference 118" data-doi="10.1111/tan.14135">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXjtFKltbw%3D" aria-label="CAS reference 118">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33179437" aria-label="PubMed reference 118">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 118" href="http://scholar.google.com/scholar_lookup?&title=Association%20of%20HLA-B22%20serotype%20with%20SARS-CoV-2%20susceptibility%20in%20Hong%20Kong%20Chinese%20patients&journal=HLA&doi=10.1111%2Ftan.14135&volume=97&pages=127-132&publication_year=2021&author=Yung%2CYL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="119."><p class="c-article-references__text" id="ref-CR119">Barquera, R. et al. Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide. <i>HLA</i> <b>96</b>, 277–298 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/tan.13956" data-track-item_id="10.1111/tan.13956" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Ftan.13956" aria-label="Article reference 119" data-doi="10.1111/tan.13956">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhslSmtL3I" aria-label="CAS reference 119">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32475052" aria-label="PubMed reference 119">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 119" href="http://scholar.google.com/scholar_lookup?&title=Binding%20affinities%20of%20438%20HLA%20proteins%20to%20complete%20proteomes%20of%20seven%20pandemic%20viruses%20and%20distributions%20of%20strongest%20and%20weakest%20HLA%20peptide%20binders%20in%20populations%20worldwide&journal=HLA&doi=10.1111%2Ftan.13956&volume=96&pages=277-298&publication_year=2020&author=Barquera%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="120."><p class="c-article-references__text" id="ref-CR120">Mohammadpour, S., Torshizi Esfahani, A., Halaji, M., Lak, M. & Ranjbar, R. An updated review of the association of host genetic factors with susceptibility and resistance to COVID-19. <i>J. Cell. Physiol.</i> <b>236</b>, 49–54 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtFKisb%2FK" aria-label="CAS reference 120">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32542735" aria-label="PubMed reference 120">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 120" href="http://scholar.google.com/scholar_lookup?&title=An%20updated%20review%20of%20the%20association%20of%20host%20genetic%20factors%20with%20susceptibility%20and%20resistance%20to%20COVID-19&journal=J.%20Cell.%20Physiol.&volume=236&pages=49-54&publication_year=2021&author=Mohammadpour%2CS&author=Torshizi%20Esfahani%2CA&author=Halaji%2CM&author=Lak%2CM&author=Ranjbar%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="121."><p class="c-article-references__text" id="ref-CR121">Debnath, M., Banerjee, M. & Berk, M. Genetic gateways to COVID-19 infection: implications for risk, severity, and outcomes. <i>FASEB J.</i> <b>34</b>, 8787–8795 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1096/fj.202001115R" data-track-item_id="10.1096/fj.202001115R" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1096%2Ffj.202001115R" aria-label="Article reference 121" data-doi="10.1096/fj.202001115R">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32525600" aria-label="PubMed reference 121">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 121" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20gateways%20to%20COVID-19%20infection%3A%20implications%20for%20risk%2C%20severity%2C%20and%20outcomes&journal=FASEB%20J.&doi=10.1096%2Ffj.202001115R&volume=34&pages=8787-8795&publication_year=2020&author=Debnath%2CM&author=Banerjee%2CM&author=Berk%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="122."><p class="c-article-references__text" id="ref-CR122">Kiyotani, K., Toyoshima, Y., Nemoto, K. & Nakamura, Y. Bioinformatic prediction of potential T cell epitopes for SARS-CoV-2. <i>J. Hum. Genet.</i> <b>65</b>, 569–575 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s10038-020-0771-5" data-track-item_id="10.1038/s10038-020-0771-5" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs10038-020-0771-5" aria-label="Article reference 122" data-doi="10.1038/s10038-020-0771-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXoslOktLw%3D" aria-label="CAS reference 122">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32372051" aria-label="PubMed reference 122">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200206" aria-label="PubMed Central reference 122">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 122" href="http://scholar.google.com/scholar_lookup?&title=Bioinformatic%20prediction%20of%20potential%20T%20cell%20epitopes%20for%20SARS-CoV-2&journal=J.%20Hum.%20Genet.&doi=10.1038%2Fs10038-020-0771-5&volume=65&pages=569-575&publication_year=2020&author=Kiyotani%2CK&author=Toyoshima%2CY&author=Nemoto%2CK&author=Nakamura%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="123."><p class="c-article-references__text" id="ref-CR123">Littera, R. et al. Human leukocyte antigen complex and other immunogenetic and clinical factors influence susceptibility or protection to SARS-CoV-2 infection and severity of the disease course. The Sardinian experience. <i>Front. Immunol.</i> <b>11</b>, 605688 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fimmu.2020.605688" data-track-item_id="10.3389/fimmu.2020.605688" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffimmu.2020.605688" aria-label="Article reference 123" data-doi="10.3389/fimmu.2020.605688">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXitVCmsbc%3D" aria-label="CAS reference 123">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33343579" aria-label="PubMed reference 123">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746644" aria-label="PubMed Central reference 123">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 123" href="http://scholar.google.com/scholar_lookup?&title=Human%20leukocyte%20antigen%20complex%20and%20other%20immunogenetic%20and%20clinical%20factors%20influence%20susceptibility%20or%20protection%20to%20SARS-CoV-2%20infection%20and%20severity%20of%20the%20disease%20course.%20The%20Sardinian%20experience&journal=Front.%20Immunol.&doi=10.3389%2Ffimmu.2020.605688&volume=11&publication_year=2020&author=Littera%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="124."><p class="c-article-references__text" id="ref-CR124">Kolin, D. A., Kulm, S., Christos, P. J. & Elemento, O. Clinical, regional, and genetic characteristics of Covid-19 patients from UK Biobank. <i>PLoS One</i> <b>15</b>, e0241264 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1371/journal.pone.0241264" data-track-item_id="10.1371/journal.pone.0241264" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1371%2Fjournal.pone.0241264" aria-label="Article reference 124" data-doi="10.1371/journal.pone.0241264">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitlyqsLvK" aria-label="CAS reference 124">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33201886" aria-label="PubMed reference 124">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671499" aria-label="PubMed Central reference 124">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 124" href="http://scholar.google.com/scholar_lookup?&title=Clinical%2C%20regional%2C%20and%20genetic%20characteristics%20of%20Covid-19%20patients%20from%20UK%20Biobank&journal=PLoS%20One&doi=10.1371%2Fjournal.pone.0241264&volume=15&publication_year=2020&author=Kolin%2CDA&author=Kulm%2CS&author=Christos%2CPJ&author=Elemento%2CO"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="125."><p class="c-article-references__text" id="ref-CR125">Wang, W., Zhang, W., Zhang, J., He, J. & Zhu, F. Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease-2019 (COVID-19). <i>HLA</i> <b>96</b>, 194–196 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/tan.13941" data-track-item_id="10.1111/tan.13941" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Ftan.13941" aria-label="Article reference 125" data-doi="10.1111/tan.13941">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVWnur7O" aria-label="CAS reference 125">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32424945" aria-label="PubMed reference 125">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 125" href="http://scholar.google.com/scholar_lookup?&title=Distribution%20of%20HLA%20allele%20frequencies%20in%2082%20Chinese%20individuals%20with%20coronavirus%20disease-2019%20%28COVID-19%29&journal=HLA&doi=10.1111%2Ftan.13941&volume=96&pages=194-196&publication_year=2020&author=Wang%2CW&author=Zhang%2CW&author=Zhang%2CJ&author=He%2CJ&author=Zhu%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="126."><p class="c-article-references__text" id="ref-CR126">Novelli, A. et al. HLA allele frequencies and susceptibility to COVID-19 in a group of 99 Italian patients. <i>HLA</i> <b>96</b>, 610–614 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/tan.14047" data-track-item_id="10.1111/tan.14047" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Ftan.14047" aria-label="Article reference 126" data-doi="10.1111/tan.14047">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitlGltb7E" aria-label="CAS reference 126">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32827207" aria-label="PubMed reference 126">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 126" href="http://scholar.google.com/scholar_lookup?&title=HLA%20allele%20frequencies%20and%20susceptibility%20to%20COVID-19%20in%20a%20group%20of%2099%20Italian%20patients&journal=HLA&doi=10.1111%2Ftan.14047&volume=96&pages=610-614&publication_year=2020&author=Novelli%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="127."><p class="c-article-references__text" id="ref-CR127">Correale, P. et al. HLA-B*44 and C*01 prevalence correlates with COVID-19 spreading across Italy. <i>Int. J. Mol. Sci.</i> <b>21</b>, 5205 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/ijms21155205" data-track-item_id="10.3390/ijms21155205" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fijms21155205" aria-label="Article reference 127" data-doi="10.3390/ijms21155205">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitValsbbM" aria-label="CAS reference 127">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432860" aria-label="PubMed Central reference 127">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 127" href="http://scholar.google.com/scholar_lookup?&title=HLA-B%2A44%20and%20C%2A01%20prevalence%20correlates%20with%20COVID-19%20spreading%20across%20Italy&journal=Int.%20J.%20Mol.%20Sci.&doi=10.3390%2Fijms21155205&volume=21&publication_year=2020&author=Correale%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="128."><p class="c-article-references__text" id="ref-CR128">Dijkstra, J., Frenette, A. & Dixon, B. Most Japanese individuals are genetically predisposed to recognize an immunogenic protein fragment shared between COVID-19 and common cold coronaviruses. <i>F1000Res.</i> <b>10</b>, 196 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.12688/f1000research.51479.1" data-track-item_id="10.12688/f1000research.51479.1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.12688%2Ff1000research.51479.1" aria-label="Article reference 128" data-doi="10.12688/f1000research.51479.1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=34026045" aria-label="PubMed reference 128">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108557" aria-label="PubMed Central reference 128">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 128" href="http://scholar.google.com/scholar_lookup?&title=Most%20Japanese%20individuals%20are%20genetically%20predisposed%20to%20recognize%20an%20immunogenic%20protein%20fragment%20shared%20between%20COVID-19%20and%20common%20cold%20coronaviruses&journal=F1000Res.&doi=10.12688%2Ff1000research.51479.1&volume=10&publication_year=2021&author=Dijkstra%2CJ&author=Frenette%2CA&author=Dixon%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="129."><p class="c-article-references__text" id="ref-CR129">Iturrieta-Zuazo, I. et al. Possible role of HLA class-I genotype in SARS-CoV-2 infection and progression: a pilot study in a cohort of Covid-19 Spanish patients. <i>Clin. Immunol.</i> <b>219</b>, 108572 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.clim.2020.108572" data-track-item_id="10.1016/j.clim.2020.108572" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.clim.2020.108572" aria-label="Article reference 129" data-doi="10.1016/j.clim.2020.108572">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhslWjtbbO" aria-label="CAS reference 129">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32810602" aria-label="PubMed reference 129">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428760" aria-label="PubMed Central reference 129">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 129" href="http://scholar.google.com/scholar_lookup?&title=Possible%20role%20of%20HLA%20class-I%20genotype%20in%20SARS-CoV-2%20infection%20and%20progression%3A%20a%20pilot%20study%20in%20a%20cohort%20of%20Covid-19%20Spanish%20patients&journal=Clin.%20Immunol.&doi=10.1016%2Fj.clim.2020.108572&volume=219&publication_year=2020&author=Iturrieta-Zuazo%2CI"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="130."><p class="c-article-references__text" id="ref-CR130">Pisanti, S. et al. Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of COVID-19. <i>J. Transl. Med.</i> <b>18</b>, 352 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12967-020-02515-5" data-track-item_id="10.1186/s12967-020-02515-5" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12967-020-02515-5" aria-label="Article reference 130" data-doi="10.1186/s12967-020-02515-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhvVKmu7fO" aria-label="CAS reference 130">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32933522" aria-label="PubMed reference 130">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491019" aria-label="PubMed Central reference 130">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 130" href="http://scholar.google.com/scholar_lookup?&title=Correlation%20of%20the%20two%20most%20frequent%20HLA%20haplotypes%20in%20the%20Italian%20population%20to%20the%20differential%20regional%20incidence%20of%20COVID-19&journal=J.%20Transl.%20Med.&doi=10.1186%2Fs12967-020-02515-5&volume=18&publication_year=2020&author=Pisanti%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="131."><p class="c-article-references__text" id="ref-CR131">Prachar, M. et al. Identification and validation of 174 COVID-19 vaccine candidate epitopes reveals low performance of common epitope prediction tools. <i>Sci. Rep.</i> <b>10</b>, 20465 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41598-020-77466-4" data-track-item_id="10.1038/s41598-020-77466-4" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41598-020-77466-4" aria-label="Article reference 131" data-doi="10.1038/s41598-020-77466-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisVOltL3L" aria-label="CAS reference 131">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33235258" aria-label="PubMed reference 131">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686376" aria-label="PubMed Central reference 131">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 131" href="http://scholar.google.com/scholar_lookup?&title=Identification%20and%20validation%20of%20174%20COVID-19%20vaccine%20candidate%20epitopes%20reveals%20low%20performance%20of%20common%20epitope%20prediction%20tools&journal=Sci.%20Rep.&doi=10.1038%2Fs41598-020-77466-4&volume=10&publication_year=2020&author=Prachar%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="132."><p class="c-article-references__text" id="ref-CR132">Liu, N. et al. The impact of ABO blood group on COVID-19 infection risk and mortality: a systematic review and meta-analysis. <i>Blood Rev.</i> <b>48</b>, 100785 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.blre.2020.100785" data-track-item_id="10.1016/j.blre.2020.100785" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.blre.2020.100785" aria-label="Article reference 132" data-doi="10.1016/j.blre.2020.100785">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33309392" aria-label="PubMed reference 132">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834371" aria-label="PubMed Central reference 132">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1WqtLvM" aria-label="CAS reference 132">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 132" href="http://scholar.google.com/scholar_lookup?&title=The%20impact%20of%20ABO%20blood%20group%20on%20COVID-19%20infection%20risk%20and%20mortality%3A%20a%20systematic%20review%20and%20meta-analysis&journal=Blood%20Rev.&doi=10.1016%2Fj.blre.2020.100785&volume=48&publication_year=2020&author=Liu%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="133."><p class="c-article-references__text" id="ref-CR133">Fan, Q. et al. Association between ABO blood group system and COVID-19 susceptibility in Wuhan. <i>Front. Cell. Infect. Microbiol.</i> <b>10</b>, 404 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fcimb.2020.00404" data-track-item_id="10.3389/fcimb.2020.00404" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffcimb.2020.00404" aria-label="Article reference 133" data-doi="10.3389/fcimb.2020.00404">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFCru7%2FO" aria-label="CAS reference 133">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32793517" aria-label="PubMed reference 133">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385064" aria-label="PubMed Central reference 133">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 133" href="http://scholar.google.com/scholar_lookup?&title=Association%20between%20ABO%20blood%20group%20system%20and%20COVID-19%20susceptibility%20in%20Wuhan&journal=Front.%20Cell.%20Infect.%20Microbiol.&doi=10.3389%2Ffcimb.2020.00404&volume=10&publication_year=2020&author=Fan%2CQ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="134."><p class="c-article-references__text" id="ref-CR134">Valenti, L. et al. Association of ABO blood group and secretor phenotype with severe COVID-19. <i>Transfusion</i> <b>60</b>, 3067–3070 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/trf.16130" data-track-item_id="10.1111/trf.16130" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Ftrf.16130" aria-label="Article reference 134" data-doi="10.1111/trf.16130">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1aju73P" aria-label="CAS reference 134">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33009662" aria-label="PubMed reference 134">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 134" href="http://scholar.google.com/scholar_lookup?&title=Association%20of%20ABO%20blood%20group%20and%20secretor%20phenotype%20with%20severe%20COVID-19&journal=Transfusion&doi=10.1111%2Ftrf.16130&volume=60&pages=3067-3070&publication_year=2020&author=Valenti%2CL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="135."><p class="c-article-references__text" id="ref-CR135">Dai, X. ABO blood group predisposes to COVID-19 severity and cardiovascular diseases. <i>Eur. J. Prev. Cardiol.</i> <b>27</b>, 1436–1437 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1177/2047487320922370" data-track-item_id="10.1177/2047487320922370" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1177%2F2047487320922370" aria-label="Article reference 135" data-doi="10.1177/2047487320922370">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32343152" aria-label="PubMed reference 135">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717262" aria-label="PubMed Central reference 135">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 135" href="http://scholar.google.com/scholar_lookup?&title=ABO%20blood%20group%20predisposes%20to%20COVID-19%20severity%20and%20cardiovascular%20diseases&journal=Eur.%20J.%20Prev.%20Cardiol.&doi=10.1177%2F2047487320922370&volume=27&pages=1436-1437&publication_year=2020&author=Dai%2CX"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="136."><p class="c-article-references__text" id="ref-CR136">Franchini, M., Crestani, S., Frattini, F., Sissa, C. & Bonfanti, C. ABO blood group and von Willebrand factor: biological implications. <i>Clin. Chem. Lab. Med.</i> <b>52</b>, 1273–1276 (2014).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1515/cclm-2014-0564" data-track-item_id="10.1515/cclm-2014-0564" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1515%2Fcclm-2014-0564" aria-label="Article reference 136" data-doi="10.1515/cclm-2014-0564">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXhtlWktbzN" aria-label="CAS reference 136">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24945431" aria-label="PubMed reference 136">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 136" href="http://scholar.google.com/scholar_lookup?&title=ABO%20blood%20group%20and%20von%20Willebrand%20factor%3A%20biological%20implications&journal=Clin.%20Chem.%20Lab.%20Med.&doi=10.1515%2Fcclm-2014-0564&volume=52&pages=1273-1276&publication_year=2014&author=Franchini%2CM&author=Crestani%2CS&author=Frattini%2CF&author=Sissa%2CC&author=Bonfanti%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="137."><p class="c-article-references__text" id="ref-CR137">Terao, C. et al. Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus. <i>Ann. Hum. Genet.</i> <b>77</b>, 465–471 (2013).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/ahg.12034" data-track-item_id="10.1111/ahg.12034" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fahg.12034" aria-label="Article reference 137" data-doi="10.1111/ahg.12034">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXhvVGhsbvL" aria-label="CAS reference 137">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23937567" aria-label="PubMed reference 137">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 137" href="http://scholar.google.com/scholar_lookup?&title=Quantitative%20variation%20in%20plasma%20angiotensin-I%20converting%20enzyme%20activity%20shows%20allelic%20heterogeneity%20in%20the%20ABO%20blood%20group%20locus&journal=Ann.%20Hum.%20Genet.&doi=10.1111%2Fahg.12034&volume=77&pages=465-471&publication_year=2013&author=Terao%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="138."><p class="c-article-references__text" id="ref-CR138">Chung, C. M. et al. A genome-wide association study identifies new loci for ACE activity: potential implications for response to ACE inhibitor. <i>Pharmacogenomics J.</i> <b>10</b>, 537–544 (2010).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/tpj.2009.70" data-track-item_id="10.1038/tpj.2009.70" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Ftpj.2009.70" aria-label="Article reference 138" data-doi="10.1038/tpj.2009.70">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXksFGrsg%3D%3D" aria-label="CAS reference 138">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=20066004" aria-label="PubMed reference 138">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 138" href="http://scholar.google.com/scholar_lookup?&title=A%20genome-wide%20association%20study%20identifies%20new%20loci%20for%20ACE%20activity%3A%20potential%20implications%20for%20response%20to%20ACE%20inhibitor&journal=Pharmacogenomics%20J.&doi=10.1038%2Ftpj.2009.70&volume=10&pages=537-544&publication_year=2010&author=Chung%2CCM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="139."><p class="c-article-references__text" id="ref-CR139">Yamagata University Genomic Cohort Consortium (YUGCC) Pleiotropic effect of common variants at ABO Glycosyltranferase locus in 9q32 on plasma levels of pancreatic lipase and angiotensin converting enzyme. <i>PLoS One</i> <b>9</b>, e55903 (2014).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="140."><p class="c-article-references__text" id="ref-CR140">Mele, D. A., Bista, P., Baez, D. V. & Huber, B. T. Dipeptidyl peptidase 2 is an essential survival factor in the regulation of cell quiescence. <i>Cell Cycle</i> <b>8</b>, 2425–2434 (2009).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.4161/cc.8.15.9144" data-track-item_id="10.4161/cc.8.15.9144" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.4161%2Fcc.8.15.9144" aria-label="Article reference 140" data-doi="10.4161/cc.8.15.9144">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3cXjtV2ks7s%3D" aria-label="CAS reference 140">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19556882" aria-label="PubMed reference 140">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 140" href="http://scholar.google.com/scholar_lookup?&title=Dipeptidyl%20peptidase%202%20is%20an%20essential%20survival%20factor%20in%20the%20regulation%20of%20cell%20quiescence&journal=Cell%20Cycle&doi=10.4161%2Fcc.8.15.9144&volume=8&pages=2425-2434&publication_year=2009&author=Mele%2CDA&author=Bista%2CP&author=Baez%2CDV&author=Huber%2CBT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="141."><p class="c-article-references__text" id="ref-CR141">Pati, A., Padhi, S., Suvankar, S. & Panda, A. K. Minor allele of interferon-induced transmembrane protein 3 polymorphism (rs12252) is covered against severe acute respiratory syndrome coronavirus 2 infection and mortality: a worldwide epidemiological investigation. <i>J. Infect. Dis.</i> <b>223</b>, 175–178 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/infdis/jiaa630" data-track-item_id="10.1093/infdis/jiaa630" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Finfdis%2Fjiaa630" aria-label="Article reference 141" data-doi="10.1093/infdis/jiaa630">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXotVaqsg%3D%3D" aria-label="CAS reference 141">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33011811" aria-label="PubMed reference 141">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 141" href="http://scholar.google.com/scholar_lookup?&title=Minor%20allele%20of%20interferon-induced%20transmembrane%20protein%203%20polymorphism%20%28rs12252%29%20is%20covered%20against%20severe%20acute%20respiratory%20syndrome%20coronavirus%202%20infection%20and%20mortality%3A%20a%20worldwide%20epidemiological%20investigation&journal=J.%20Infect.%20Dis.&doi=10.1093%2Finfdis%2Fjiaa630&volume=223&pages=175-178&publication_year=2021&author=Pati%2CA&author=Padhi%2CS&author=Suvankar%2CS&author=Panda%2CAK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="142."><p class="c-article-references__text" id="ref-CR142">Zhang, Y. et al. Interferon-induced transmembrane protein 3 genetic variant rs12252-C associated with disease severity in coronavirus disease 2019. <i>J. Infect. Dis.</i> <b>222</b>, 34–37 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/infdis/jiaa224" data-track-item_id="10.1093/infdis/jiaa224" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Finfdis%2Fjiaa224" aria-label="Article reference 142" data-doi="10.1093/infdis/jiaa224">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32348495" aria-label="PubMed reference 142">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197559" aria-label="PubMed Central reference 142">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXht1KrsbjM" aria-label="CAS reference 142">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 142" href="http://scholar.google.com/scholar_lookup?&title=Interferon-induced%20transmembrane%20protein%203%20genetic%20variant%20rs12252-C%20associated%20with%20disease%20severity%20in%20coronavirus%20disease%202019&journal=J.%20Infect.%20Dis.&doi=10.1093%2Finfdis%2Fjiaa224&volume=222&pages=34-37&publication_year=2020&author=Zhang%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="143."><p class="c-article-references__text" id="ref-CR143">Thevarajan, I. et al. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. <i>Nat. Med.</i> <b>26</b>, 453–455 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41591-020-0819-2" data-track-item_id="10.1038/s41591-020-0819-2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41591-020-0819-2" aria-label="Article reference 143" data-doi="10.1038/s41591-020-0819-2">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXltFShtr8%3D" aria-label="CAS reference 143">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32284614" aria-label="PubMed reference 143">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 143" href="http://scholar.google.com/scholar_lookup?&title=Breadth%20of%20concomitant%20immune%20responses%20prior%20to%20patient%20recovery%3A%20a%20case%20report%20of%20non-severe%20COVID-19&journal=Nat.%20Med.&doi=10.1038%2Fs41591-020-0819-2&volume=26&pages=453-455&publication_year=2020&author=Thevarajan%2CI"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="144."><p class="c-article-references__text" id="ref-CR144">Gómez, J. et al. The interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19. <i>Cytokine</i> <b>137</b>, 155354 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cyto.2020.155354" data-track-item_id="10.1016/j.cyto.2020.155354" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cyto.2020.155354" aria-label="Article reference 144" data-doi="10.1016/j.cyto.2020.155354">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33113474" aria-label="PubMed reference 144">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitFyhsbnK" aria-label="CAS reference 144">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 144" href="http://scholar.google.com/scholar_lookup?&title=The%20interferon-induced%20transmembrane%20protein%203%20gene%20%28IFITM3%29%20rs12252%20C%20variant%20is%20associated%20with%20COVID-19&journal=Cytokine&doi=10.1016%2Fj.cyto.2020.155354&volume=137&publication_year=2021&author=G%C3%B3mez%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="145."><p class="c-article-references__text" id="ref-CR145">Nikoloudis, D., Kountouras, D. & Hiona, A. The frequency of combined IFITM3 haplotype involving the reference alleles of both rs12252 and rs34481144 is in line with COVID-19 standardized mortality ratio of ethnic groups in England. <i>PeerJ</i> <b>8</b>, e10402 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7717/peerj.10402" data-track-item_id="10.7717/peerj.10402" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7717%2Fpeerj.10402" aria-label="Article reference 145" data-doi="10.7717/peerj.10402">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33240681" aria-label="PubMed reference 145">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666821" aria-label="PubMed Central reference 145">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 145" href="http://scholar.google.com/scholar_lookup?&title=The%20frequency%20of%20combined%20IFITM3%20haplotype%20involving%20the%20reference%20alleles%20of%20both%20rs12252%20and%20rs34481144%20is%20in%20line%20with%20COVID-19%20standardized%20mortality%20ratio%20of%20ethnic%20groups%20in%20England&journal=PeerJ&doi=10.7717%2Fpeerj.10402&volume=8&publication_year=2020&author=Nikoloudis%2CD&author=Kountouras%2CD&author=Hiona%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="146."><p class="c-article-references__text" id="ref-CR146">Allen, E. K. et al. SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans. <i>Nat. Med.</i> <b>23</b>, 975–983 (2017).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nm.4370" data-track-item_id="10.1038/nm.4370" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnm.4370" aria-label="Article reference 146" data-doi="10.1038/nm.4370">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2sXhtFOru7nP" aria-label="CAS reference 146">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=28714988" aria-label="PubMed reference 146">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702558" aria-label="PubMed Central reference 146">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 146" href="http://scholar.google.com/scholar_lookup?&title=SNP-mediated%20disruption%20of%20CTCF%20binding%20at%20the%20IFITM3%20promoter%20is%20associated%20with%20risk%20of%20severe%20influenza%20in%20humans&journal=Nat.%20Med.&doi=10.1038%2Fnm.4370&volume=23&pages=975-983&publication_year=2017&author=Allen%2CEK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="147."><p class="c-article-references__text" id="ref-CR147">Bentson, L. F. et al. New point mutation in Golga3 causes multiple defects in spermatogenesis. <i>Andrology</i> <b>1</b>, 440–450 (2013).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/j.2047-2927.2013.00070.x" data-track-item_id="10.1111/j.2047-2927.2013.00070.x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fj.2047-2927.2013.00070.x" aria-label="Article reference 147" data-doi="10.1111/j.2047-2927.2013.00070.x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXmt1KqtL4%3D" aria-label="CAS reference 147">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23495255" aria-label="PubMed reference 147">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134951" aria-label="PubMed Central reference 147">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 147" href="http://scholar.google.com/scholar_lookup?&title=New%20point%20mutation%20in%20Golga3%20causes%20multiple%20defects%20in%20spermatogenesis&journal=Andrology&doi=10.1111%2Fj.2047-2927.2013.00070.x&volume=1&pages=440-450&publication_year=2013&author=Bentson%2CLF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="148."><p class="c-article-references__text" id="ref-CR148">Gordon, D. E. et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. <i>Nature</i> <b>583</b>, 459–468 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41586-020-2286-9" data-track-item_id="10.1038/s41586-020-2286-9" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41586-020-2286-9" aria-label="Article reference 148" data-doi="10.1038/s41586-020-2286-9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtlCqtbrI" aria-label="CAS reference 148">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32353859" aria-label="PubMed reference 148">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431030" aria-label="PubMed Central reference 148">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 148" href="http://scholar.google.com/scholar_lookup?&title=A%20SARS-CoV-2%20protein%20interaction%20map%20reveals%20targets%20for%20drug%20repurposing&journal=Nature&doi=10.1038%2Fs41586-020-2286-9&volume=583&pages=459-468&publication_year=2020&author=Gordon%2CDE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="149."><p class="c-article-references__text" id="ref-CR149">Wei, J. et al. Genome-wide CRISPR screens reveal host factors critical for SARS-CoV-2 infection. <i>Cell</i> <b>184</b>, 76–91.e13 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cell.2020.10.028" data-track-item_id="10.1016/j.cell.2020.10.028" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cell.2020.10.028" aria-label="Article reference 149" data-doi="10.1016/j.cell.2020.10.028">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit1GqsLrO" aria-label="CAS reference 149">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33147444" aria-label="PubMed reference 149">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 149" href="http://scholar.google.com/scholar_lookup?&title=Genome-wide%20CRISPR%20screens%20reveal%20host%20factors%20critical%20for%20SARS-CoV-2%20infection&journal=Cell&doi=10.1016%2Fj.cell.2020.10.028&volume=184&pages=76-91.e13&publication_year=2021&author=Wei%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="150."><p class="c-article-references__text" id="ref-CR150">Chen, R. et al. HMGB1 as a potential biomarker and therapeutic target for severe COVID-19. <i>Heliyon</i> <b>6</b>, e05672 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.heliyon.2020.e05672" data-track-item_id="10.1016/j.heliyon.2020.e05672" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.heliyon.2020.e05672" aria-label="Article reference 150" data-doi="10.1016/j.heliyon.2020.e05672">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33313438" aria-label="PubMed reference 150">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720697" aria-label="PubMed Central reference 150">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 150" href="http://scholar.google.com/scholar_lookup?&title=HMGB1%20as%20a%20potential%20biomarker%20and%20therapeutic%20target%20for%20severe%20COVID-19&journal=Heliyon&doi=10.1016%2Fj.heliyon.2020.e05672&volume=6&publication_year=2020&author=Chen%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="151."><p class="c-article-references__text" id="ref-CR151">Al-Mulla, F. et al. ACE2 and FURIN variants are potential predictors of SARS-CoV-2 outcome: a time to implement precision medicine against COVID-19. <i>Heliyon</i> <b>7</b>, e06133 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.heliyon.2021.e06133" data-track-item_id="10.1016/j.heliyon.2021.e06133" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.heliyon.2021.e06133" aria-label="Article reference 151" data-doi="10.1016/j.heliyon.2021.e06133">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33532652" aria-label="PubMed reference 151">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843038" aria-label="PubMed Central reference 151">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 151" href="http://scholar.google.com/scholar_lookup?&title=ACE2%20and%20FURIN%20variants%20are%20potential%20predictors%20of%20SARS-CoV-2%20outcome%3A%20a%20time%20to%20implement%20precision%20medicine%20against%20COVID-19&journal=Heliyon&doi=10.1016%2Fj.heliyon.2021.e06133&volume=7&publication_year=2021&author=Al-Mulla%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="152."><p class="c-article-references__text" id="ref-CR152">Gemmati, D. & Tisato, V. Genetic hypothesis and pharmacogenetics side of renin-angiotensin-system in COVID-19. <i>Genes</i> <b>11</b>, 1044 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/genes11091044" data-track-item_id="10.3390/genes11091044" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fgenes11091044" aria-label="Article reference 152" data-doi="10.3390/genes11091044">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFKmtLrK" aria-label="CAS reference 152">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563402" aria-label="PubMed Central reference 152">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 152" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20hypothesis%20and%20pharmacogenetics%20side%20of%20renin-angiotensin-system%20in%20COVID-19&journal=Genes&doi=10.3390%2Fgenes11091044&volume=11&publication_year=2020&author=Gemmati%2CD&author=Tisato%2CV"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="153."><p class="c-article-references__text" id="ref-CR153">Purwaningroom, D. L., Saifurrohman, M., Widodo, Putri, J. F. & Lukitasari, M. Alteration of splicing pattern on angiotensin-converting enzyme gene due to the insertion of Alu elements. <i>IJCB</i> <b>4</b>, 53–58 (2015).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 153" href="http://scholar.google.com/scholar_lookup?&title=Alteration%20of%20splicing%20pattern%20on%20angiotensin-converting%20enzyme%20gene%20due%20to%20the%20insertion%20of%20Alu%20elements&journal=IJCB&volume=4&pages=53-58&publication_year=2015&author=Purwaningroom%2CDL&author=Saifurrohman%2CM&author=Widodo%2C&author=Putri%2CJF&author=Lukitasari%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="154."><p class="c-article-references__text" id="ref-CR154">Gemmati, D. et al. COVID-19 and individual genetic susceptibility/receptivity: role of ACE1/ACE2 genes, immunity, inflammation and coagulation. Might the double X-chromosome in females be protective against SARS-CoV-2 compared to the single X-chromosome in males? <i>Int. J. Mol. Sci.</i> <b>21</b>, 3474 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/ijms21103474" data-track-item_id="10.3390/ijms21103474" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fijms21103474" aria-label="Article reference 154" data-doi="10.3390/ijms21103474">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhvF2gtrvK" aria-label="CAS reference 154">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278991" aria-label="PubMed Central reference 154">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 154" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20and%20individual%20genetic%20susceptibility%2Freceptivity%3A%20role%20of%20ACE1%2FACE2%20genes%2C%20immunity%2C%20inflammation%20and%20coagulation.%20Might%20the%20double%20X-chromosome%20in%20females%20be%20protective%20against%20SARS-CoV-2%20compared%20to%20the%20single%20X-chromosome%20in%20males%3F&journal=Int.%20J.%20Mol.%20Sci.&doi=10.3390%2Fijms21103474&volume=21&publication_year=2020&author=Gemmati%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="155."><p class="c-article-references__text" id="ref-CR155">Zheng, H. & Cao, J. J. Angiotensin-converting enzyme gene polymorphism and severe lung injury in patients with coronavirus disease 2019. <i>Am. J. Pathol.</i> <b>190</b>, 2013–2017 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.ajpath.2020.07.009" data-track-item_id="10.1016/j.ajpath.2020.07.009" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.ajpath.2020.07.009" aria-label="Article reference 155" data-doi="10.1016/j.ajpath.2020.07.009">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhs1ejtrbF" aria-label="CAS reference 155">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32735889" aria-label="PubMed reference 155">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 155" href="http://scholar.google.com/scholar_lookup?&title=Angiotensin-converting%20enzyme%20gene%20polymorphism%20and%20severe%20lung%20injury%20in%20patients%20with%20coronavirus%20disease%202019&journal=Am.%20J.%20Pathol.&doi=10.1016%2Fj.ajpath.2020.07.009&volume=190&pages=2013-2017&publication_year=2020&author=Zheng%2CH&author=Cao%2CJJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="156."><p class="c-article-references__text" id="ref-CR156">Delanghe, J. R., Speeckaert, M. M. & De Buyzere, M. L. COVID-19 infections are also affected by human ACE1 D/I polymorphism. <i>Clin. Chem. Lab. Med.</i> <b>58</b>, 1125–1126 (2020).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="157."><p class="c-article-references__text" id="ref-CR157">Delanghe, J. R., Speeckaert, M. M. & De Buyzere, M. L. The host’s angiotensin-converting enzyme polymorphism may explain epidemiological findings in COVID-19 infections. <i>Clin. Chim. Acta</i> <b>505</b>, 192–193 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cca.2020.03.031" data-track-item_id="10.1016/j.cca.2020.03.031" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cca.2020.03.031" aria-label="Article reference 157" data-doi="10.1016/j.cca.2020.03.031">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXmtFOqtLw%3D" aria-label="CAS reference 157">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32220422" aria-label="PubMed reference 157">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102561" aria-label="PubMed Central reference 157">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 157" href="http://scholar.google.com/scholar_lookup?&title=The%20host%E2%80%99s%20angiotensin-converting%20enzyme%20polymorphism%20may%20explain%20epidemiological%20findings%20in%20COVID-19%20infections&journal=Clin.%20Chim.%20Acta&doi=10.1016%2Fj.cca.2020.03.031&volume=505&pages=192-193&publication_year=2020&author=Delanghe%2CJR&author=Speeckaert%2CMM&author=Buyzere%2CML"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="158."><p class="c-article-references__text" id="ref-CR158">Hatami, N. et al. Worldwide ACE (I/D) polymorphism may affect COVID-19 recovery rate: an ecological meta-regression. <i>Endocrine</i> <b>68</b>, 479–484 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s12020-020-02381-7" data-track-item_id="10.1007/s12020-020-02381-7" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s12020-020-02381-7" aria-label="Article reference 158" data-doi="10.1007/s12020-020-02381-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtFKgtrrF" aria-label="CAS reference 158">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32542429" aria-label="PubMed reference 158">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294766" aria-label="PubMed Central reference 158">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 158" href="http://scholar.google.com/scholar_lookup?&title=Worldwide%20ACE%20%28I%2FD%29%20polymorphism%20may%20affect%20COVID-19%20recovery%20rate%3A%20an%20ecological%20meta-regression&journal=Endocrine&doi=10.1007%2Fs12020-020-02381-7&volume=68&pages=479-484&publication_year=2020&author=Hatami%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="159."><p class="c-article-references__text" id="ref-CR159">Li, X., Sun, X., Jin, L. & Xue, F. Worldwide spatial genetic structure of angiotensin-converting enzyme gene: a new evolutionary ecological evidence for the thrifty genotype hypothesis. <i>Eur. J. Hum. Genet.</i> <b>19</b>, 1002–1008 (2011).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/ejhg.2011.66" data-track-item_id="10.1038/ejhg.2011.66" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fejhg.2011.66" aria-label="Article reference 159" data-doi="10.1038/ejhg.2011.66">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXhtVegt7%2FJ" aria-label="CAS reference 159">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=21559052" aria-label="PubMed reference 159">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179366" aria-label="PubMed Central reference 159">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 159" href="http://scholar.google.com/scholar_lookup?&title=Worldwide%20spatial%20genetic%20structure%20of%20angiotensin-converting%20enzyme%20gene%3A%20a%20new%20evolutionary%20ecological%20evidence%20for%20the%20thrifty%20genotype%20hypothesis&journal=Eur.%20J.%20Hum.%20Genet.&doi=10.1038%2Fejhg.2011.66&volume=19&pages=1002-1008&publication_year=2011&author=Li%2CX&author=Sun%2CX&author=Jin%2CL&author=Xue%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="160."><p class="c-article-references__text" id="ref-CR160">Anastassopoulou, C., Gkizarioti, Z., Patrinos, G. P. & Tsakris, A. Human genetic factors associated with susceptibility to SARS-CoV-2 infection and COVID-19 disease severity. <i>Hum. Genomics</i> <b>14</b>, 40 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40246-020-00290-4" data-track-item_id="10.1186/s40246-020-00290-4" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40246-020-00290-4" aria-label="Article reference 160" data-doi="10.1186/s40246-020-00290-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitFOhu7zN" aria-label="CAS reference 160">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33092637" aria-label="PubMed reference 160">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578581" aria-label="PubMed Central reference 160">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 160" href="http://scholar.google.com/scholar_lookup?&title=Human%20genetic%20factors%20associated%20with%20susceptibility%20to%20SARS-CoV-2%20infection%20and%20COVID-19%20disease%20severity&journal=Hum.%20Genomics&doi=10.1186%2Fs40246-020-00290-4&volume=14&publication_year=2020&author=Anastassopoulou%2CC&author=Gkizarioti%2CZ&author=Patrinos%2CGP&author=Tsakris%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="161."><p class="c-article-references__text" id="ref-CR161">Kasparian, K., Graykowski, D. & Cudaback, E. Commentary: APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort. <i>Front. Immunol.</i> <b>11</b>, 1939 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fimmu.2020.01939" data-track-item_id="10.3389/fimmu.2020.01939" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffimmu.2020.01939" aria-label="Article reference 161" data-doi="10.3389/fimmu.2020.01939">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1CnsbvP" aria-label="CAS reference 161">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33042114" aria-label="PubMed reference 161">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522160" aria-label="PubMed Central reference 161">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 161" href="http://scholar.google.com/scholar_lookup?&title=Commentary%3A%20APOE%20e4%20genotype%20predicts%20severe%20COVID-19%20in%20the%20UK%20biobank%20community%20cohort&journal=Front.%20Immunol.&doi=10.3389%2Ffimmu.2020.01939&volume=11&publication_year=2020&author=Kasparian%2CK&author=Graykowski%2CD&author=Cudaback%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="162."><p class="c-article-references__text" id="ref-CR162">Inal, J. Biological factors linking APOE ε4 variant and severe COVID-19. <i>Curr. Atheroscler. Rep.</i> <b>22</b>, 70 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s11883-020-00896-y" data-track-item_id="10.1007/s11883-020-00896-y" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s11883-020-00896-y" aria-label="Article reference 162" data-doi="10.1007/s11883-020-00896-y">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitVags73O" aria-label="CAS reference 162">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33006059" aria-label="PubMed reference 162">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529518" aria-label="PubMed Central reference 162">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 162" href="http://scholar.google.com/scholar_lookup?&title=Biological%20factors%20linking%20APOE%20%CE%B54%20variant%20and%20severe%20COVID-19&journal=Curr.%20Atheroscler.%20Rep.&doi=10.1007%2Fs11883-020-00896-y&volume=22&publication_year=2020&author=Inal%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="163."><p class="c-article-references__text" id="ref-CR163">Kuo, C. L. et al. APOE e4 genotype predicts severe COVID-19 in the UK biobank community cohort. <i>J. Gerontol. A Biol. Sci. Med. Sci.</i> <b>75</b>, 2231–2232 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/gerona/glaa131" data-track-item_id="10.1093/gerona/glaa131" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fgerona%2Fglaa131" aria-label="Article reference 163" data-doi="10.1093/gerona/glaa131">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXosVSit7Y%3D" aria-label="CAS reference 163">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32451547" aria-label="PubMed reference 163">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314139" aria-label="PubMed Central reference 163">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 163" href="http://scholar.google.com/scholar_lookup?&title=APOE%20e4%20genotype%20predicts%20severe%20COVID-19%20in%20the%20UK%20biobank%20community%20cohort&journal=J.%20Gerontol.%20A%20Biol.%20Sci.%20Med.%20Sci.&doi=10.1093%2Fgerona%2Fglaa131&volume=75&pages=2231-2232&publication_year=2020&author=Kuo%2CCL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="164."><p class="c-article-references__text" id="ref-CR164">Alshahawey, M., Raslan, M. & Sabri, N. Sex-mediated effects of ACE2 and TMPRSS2 on the incidence and severity of COVID-19; the need for genetic implementation. <i>Curr. Res. Transl. Med.</i> <b>68</b>, 149–150 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.retram.2020.08.002" data-track-item_id="10.1016/j.retram.2020.08.002" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.retram.2020.08.002" aria-label="Article reference 164" data-doi="10.1016/j.retram.2020.08.002">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32917573" aria-label="PubMed reference 164">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474911" aria-label="PubMed Central reference 164">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 164" href="http://scholar.google.com/scholar_lookup?&title=Sex-mediated%20effects%20of%20ACE2%20and%20TMPRSS2%20on%20the%20incidence%20and%20severity%20of%20COVID-19%3B%20the%20need%20for%20genetic%20implementation&journal=Curr.%20Res.%20Transl.%20Med.&doi=10.1016%2Fj.retram.2020.08.002&volume=68&pages=149-150&publication_year=2020&author=Alshahawey%2CM&author=Raslan%2CM&author=Sabri%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="165."><p class="c-article-references__text" id="ref-CR165">Barash, A., Machluf, Y., Ariel, I. & Dekel, Y. The pursuit of COVID-19 biomarkers: putting the spotlight on ACE2 and TMPRSS2 regulatory sequences. <i>Front. Med.</i> <b>7</b>, 582793 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fmed.2020.582793" data-track-item_id="10.3389/fmed.2020.582793" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffmed.2020.582793" aria-label="Article reference 165" data-doi="10.3389/fmed.2020.582793">Article</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 165" href="http://scholar.google.com/scholar_lookup?&title=The%20pursuit%20of%20COVID-19%20biomarkers%3A%20putting%20the%20spotlight%20on%20ACE2%20and%20TMPRSS2%20regulatory%20sequences&journal=Front.%20Med.&doi=10.3389%2Ffmed.2020.582793&volume=7&publication_year=2020&author=Barash%2CA&author=Machluf%2CY&author=Ariel%2CI&author=Dekel%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="166."><p class="c-article-references__text" id="ref-CR166">Singh, H., Choudhari, R., Nema, V. & Khan, A. A. ACE2 and TMPRSS2 polymorphisms in various diseases with special reference to its impact on COVID-19 disease. <i>Microb. Pathogenesis</i> <b>150</b>, 104621 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.micpath.2020.104621" data-track-item_id="10.1016/j.micpath.2020.104621" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.micpath.2020.104621" aria-label="Article reference 166" data-doi="10.1016/j.micpath.2020.104621">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1WqtrfN" aria-label="CAS reference 166">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 166" href="http://scholar.google.com/scholar_lookup?&title=ACE2%20and%20TMPRSS2%20polymorphisms%20in%20various%20diseases%20with%20special%20reference%20to%20its%20impact%20on%20COVID-19%20disease&journal=Microb.%20Pathogenesis&doi=10.1016%2Fj.micpath.2020.104621&volume=150&publication_year=2021&author=Singh%2CH&author=Choudhari%2CR&author=Nema%2CV&author=Khan%2CAA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="167."><p class="c-article-references__text" id="ref-CR167">Yildirim, Z., Sahin, O. S., Yazar, S. & Bozok Cetintas, V. Genetic and epigenetic factors associated with increased severity of Covid-19. <i>Cell Biol. Int.</i> <b>45</b>, 1158–1174 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/cbin.11572" data-track-item_id="10.1002/cbin.11572" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fcbin.11572" aria-label="Article reference 167" data-doi="10.1002/cbin.11572">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhvVaksrnM" aria-label="CAS reference 167">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33590936" aria-label="PubMed reference 167">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 167" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20and%20epigenetic%20factors%20associated%20with%20increased%20severity%20of%20Covid-19&journal=Cell%20Biol.%20Int.&doi=10.1002%2Fcbin.11572&volume=45&pages=1158-1174&publication_year=2021&author=Yildirim%2CZ&author=Sahin%2COS&author=Yazar%2CS&author=Bozok%20Cetintas%2CV"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="168."><p class="c-article-references__text" id="ref-CR168">Choudhary, S., Sreenivasulu, K., Mitra, P., Misra, S. & Sharma, P. Role of genetic variants and gene expression in the susceptibility and severity of COVID-19. <i>Ann. Lab. Med.</i> <b>41</b>, 129–138 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3343/alm.2021.41.2.129" data-track-item_id="10.3343/alm.2021.41.2.129" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3343%2Falm.2021.41.2.129" aria-label="Article reference 168" data-doi="10.3343/alm.2021.41.2.129">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33063674" aria-label="PubMed reference 168">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591285" aria-label="PubMed Central reference 168">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 168" href="http://scholar.google.com/scholar_lookup?&title=Role%20of%20genetic%20variants%20and%20gene%20expression%20in%20the%20susceptibility%20and%20severity%20of%20COVID-19&journal=Ann.%20Lab.%20Med.&doi=10.3343%2Falm.2021.41.2.129&volume=41&pages=129-138&publication_year=2021&author=Choudhary%2CS&author=Sreenivasulu%2CK&author=Mitra%2CP&author=Misra%2CS&author=Sharma%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="169."><p class="c-article-references__text" id="ref-CR169">Irham, L. M. et al. Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents. <i>Biochem. Biophys. Res. Commun.</i> <b>529</b>, 263–269 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.bbrc.2020.05.179" data-track-item_id="10.1016/j.bbrc.2020.05.179" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.bbrc.2020.05.179" aria-label="Article reference 169" data-doi="10.1016/j.bbrc.2020.05.179">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXht1CjtLzL" aria-label="CAS reference 169">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32703421" aria-label="PubMed reference 169">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831678" aria-label="PubMed Central reference 169">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 169" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20variants%20that%20influence%20SARS-CoV-2%20receptor%20TMPRSS2%20expression%20among%20population%20cohorts%20from%20multiple%20continents&journal=Biochem.%20Biophys.%20Res.%20Commun.&doi=10.1016%2Fj.bbrc.2020.05.179&volume=529&pages=263-269&publication_year=2020&author=Irham%2CLM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="170."><p class="c-article-references__text" id="ref-CR170">Piva, F., Sabanovic, B., Cecati, M. & Giulietti, M. Expression and co-expression analyses of TMPRSS2, a key element in COVID-19. <i>Eur. J. Clin. Microbiol. Infect. Dis.</i> <b>40</b>, 451–455 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s10096-020-04089-y" data-track-item_id="10.1007/s10096-020-04089-y" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s10096-020-04089-y" aria-label="Article reference 170" data-doi="10.1007/s10096-020-04089-y">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFensbfN" aria-label="CAS reference 170">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33245471" aria-label="PubMed reference 170">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 170" href="http://scholar.google.com/scholar_lookup?&title=Expression%20and%20co-expression%20analyses%20of%20TMPRSS2%2C%20a%20key%20element%20in%20COVID-19&journal=Eur.%20J.%20Clin.%20Microbiol.%20Infect.%20Dis.&doi=10.1007%2Fs10096-020-04089-y&volume=40&pages=451-455&publication_year=2021&author=Piva%2CF&author=Sabanovic%2CB&author=Cecati%2CM&author=Giulietti%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="171."><p class="c-article-references__text" id="ref-CR171">Hou, Y. et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. <i>BMC Med.</i> <b>18</b>, 216 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12916-020-01673-z" data-track-item_id="10.1186/s12916-020-01673-z" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12916-020-01673-z" aria-label="Article reference 171" data-doi="10.1186/s12916-020-01673-z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtl2ru7%2FF" aria-label="CAS reference 171">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32664879" aria-label="PubMed reference 171">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360473" aria-label="PubMed Central reference 171">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 171" href="http://scholar.google.com/scholar_lookup?&title=New%20insights%20into%20genetic%20susceptibility%20of%20COVID-19%3A%20an%20ACE2%20and%20TMPRSS2%20polymorphism%20analysis&journal=BMC%20Med.&doi=10.1186%2Fs12916-020-01673-z&volume=18&publication_year=2020&author=Hou%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="172."><p class="c-article-references__text" id="ref-CR172">Foresta, C. & Rocca, M. S. & Di Nisio, A. Gender susceptibility to COVID-19: a review of the putative role of sex hormones and X chromosome. <i>J. Endocrinol. Invest.</i> <b>16</b>, 1–6 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 172" href="http://scholar.google.com/scholar_lookup?&title=%26%20Di%20Nisio%2C%20A.%20Gender%20susceptibility%20to%20COVID-19%3A%20a%20review%20of%20the%20putative%20role%20of%20sex%20hormones%20and%20X%20chromosome&journal=J.%20Endocrinol.%20Invest.&volume=16&pages=1-6&publication_year=2020&author=Foresta%2CC&author=Rocca%2CMS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="173."><p class="c-article-references__text" id="ref-CR173">Kloc, M., Ghobrial, R. M. & Kubiak, J. Z. The role of genetic sex and mitochondria in response to COVID-19 infection. <i>Int. Arch. Allergy Immunol.</i> <b>181</b>, 629–634 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1159/000508560" data-track-item_id="10.1159/000508560" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1159%2F000508560" aria-label="Article reference 173" data-doi="10.1159/000508560">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsFCju7zI" aria-label="CAS reference 173">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32564017" aria-label="PubMed reference 173">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 173" href="http://scholar.google.com/scholar_lookup?&title=The%20role%20of%20genetic%20sex%20and%20mitochondria%20in%20response%20to%20COVID-19%20infection&journal=Int.%20Arch.%20Allergy%20Immunol.&doi=10.1159%2F000508560&volume=181&pages=629-634&publication_year=2020&author=Kloc%2CM&author=Ghobrial%2CRM&author=Kubiak%2CJZ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="174."><p class="c-article-references__text" id="ref-CR174">Li, Y., Jerkic, M., Slutsky, A. S. & Zhang, H. Molecular mechanisms of sex bias differences in COVID-19 mortality. <i>Crit. Care</i> <b>24</b>, 405 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13054-020-03118-8" data-track-item_id="10.1186/s13054-020-03118-8" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13054-020-03118-8" aria-label="Article reference 174" data-doi="10.1186/s13054-020-03118-8">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32646459" aria-label="PubMed reference 174">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347256" aria-label="PubMed Central reference 174">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 174" href="http://scholar.google.com/scholar_lookup?&title=Molecular%20mechanisms%20of%20sex%20bias%20differences%20in%20COVID-19%20mortality&journal=Crit.%20Care&doi=10.1186%2Fs13054-020-03118-8&volume=24&publication_year=2020&author=Li%2CY&author=Jerkic%2CM&author=Slutsky%2CAS&author=Zhang%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="175."><p class="c-article-references__text" id="ref-CR175">Viveiros, A. et al. Sex differences in COVID-19: candidate pathways, genetics of ACE2, and sex hormones. <i>Am. J. Physiol. Heart Circ. Physiol.</i> <b>320</b>, H296–H304 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1152/ajpheart.00755.2020" data-track-item_id="10.1152/ajpheart.00755.2020" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1152%2Fajpheart.00755.2020" aria-label="Article reference 175" data-doi="10.1152/ajpheart.00755.2020">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXjvVylsrk%3D" aria-label="CAS reference 175">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33275517" aria-label="PubMed reference 175">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 175" href="http://scholar.google.com/scholar_lookup?&title=Sex%20differences%20in%20COVID-19%3A%20candidate%20pathways%2C%20genetics%20of%20ACE2%2C%20and%20sex%20hormones&journal=Am.%20J.%20Physiol.%20Heart%20Circ.%20Physiol.&doi=10.1152%2Fajpheart.00755.2020&volume=320&pages=H296-H304&publication_year=2021&author=Viveiros%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="176."><p class="c-article-references__text" id="ref-CR176">Gadi, N., Wu, S. C., Spihlman, A. P. & Moulton, V. R. What’s sex got to do with COVID-19? Gender-based differences in the host immune response to coronaviruses. <i>Front. Immunol.</i> <b>11</b>, 2147 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fimmu.2020.02147" data-track-item_id="10.3389/fimmu.2020.02147" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffimmu.2020.02147" aria-label="Article reference 176" data-doi="10.3389/fimmu.2020.02147">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1KjtbbO" aria-label="CAS reference 176">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32983176" aria-label="PubMed reference 176">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485092" aria-label="PubMed Central reference 176">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 176" href="http://scholar.google.com/scholar_lookup?&title=What%E2%80%99s%20sex%20got%20to%20do%20with%20COVID-19%3F%20Gender-based%20differences%20in%20the%20host%20immune%20response%20to%20coronaviruses&journal=Front.%20Immunol.&doi=10.3389%2Ffimmu.2020.02147&volume=11&publication_year=2020&author=Gadi%2CN&author=Wu%2CSC&author=Spihlman%2CAP&author=Moulton%2CVR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="177."><p class="c-article-references__text" id="ref-CR177">Wang, J. et al. Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. <i>Proc. Natl. Acad. Sci. USA</i> <b>113</b>, E2029–E2038 (2016).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XksFCmu78%3D" aria-label="CAS reference 177">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27001848" aria-label="PubMed reference 177">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833277" aria-label="PubMed Central reference 177">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 177" href="http://scholar.google.com/scholar_lookup?&title=Unusual%20maintenance%20of%20X%20chromosome%20inactivation%20predisposes%20female%20lymphocytes%20for%20increased%20expression%20from%20the%20inactive%20X&journal=Proc.%20Natl.%20Acad.%20Sci.%20USA&volume=113&pages=E2029-E2038&publication_year=2016&author=Wang%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="178."><p class="c-article-references__text" id="ref-CR178">Kelada, M., Anto, A., Dave, K. & Saleh, S. N. The role of sex in the risk of mortality from COVID-19 amongst adult patients: a systematic review. <i>Cureus</i> <b>12</b>, e10114 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33005531" aria-label="PubMed reference 178">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523740" aria-label="PubMed Central reference 178">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 178" href="http://scholar.google.com/scholar_lookup?&title=The%20role%20of%20sex%20in%20the%20risk%20of%20mortality%20from%20COVID-19%20amongst%20adult%20patients%3A%20a%20systematic%20review&journal=Cureus&volume=12&publication_year=2020&author=Kelada%2CM&author=Anto%2CA&author=Dave%2CK&author=Saleh%2CSN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="179."><p class="c-article-references__text" id="ref-CR179">Penna, C., Mercurio, V., Tocchetti, C. G. & Pagliaro, P. Sex-related differences in COVID-19 lethality. <i>Br. J. Pharmacol.</i> <b>177</b>, 4375–4385 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsFeis73I" aria-label="CAS reference 179">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32698249" aria-label="PubMed reference 179">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405496" aria-label="PubMed Central reference 179">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 179" href="http://scholar.google.com/scholar_lookup?&title=Sex-related%20differences%20in%20COVID-19%20lethality&journal=Br.%20J.%20Pharmacol.&volume=177&pages=4375-4385&publication_year=2020&author=Penna%2CC&author=Mercurio%2CV&author=Tocchetti%2CCG&author=Pagliaro%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="180."><p class="c-article-references__text" id="ref-CR180">van de Veerdonk, F. L. & Netea, M. G. Rare variants increase the risk of severe COVID-19. <i>Elife</i> <b>10</b>, e67860 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7554/eLife.67860" data-track-item_id="10.7554/eLife.67860" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7554%2FeLife.67860" aria-label="Article reference 180" data-doi="10.7554/eLife.67860">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33752797" aria-label="PubMed reference 180">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987329" aria-label="PubMed Central reference 180">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 180" href="http://scholar.google.com/scholar_lookup?&title=Rare%20variants%20increase%20the%20risk%20of%20severe%20COVID-19&journal=Elife&doi=10.7554%2FeLife.67860&volume=10&publication_year=2021&author=van%20de%20Veerdonk%2CFL&author=Netea%2CMG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="181."><p class="c-article-references__text" id="ref-CR181">van der Made, C. I. et al. Presence of genetic variants among young men with severe COVID-19. <i>JAMA</i> <b>324</b>, 663–673 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1001/jama.2020.13719" data-track-item_id="10.1001/jama.2020.13719" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1001%2Fjama.2020.13719" aria-label="Article reference 181" data-doi="10.1001/jama.2020.13719">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32706371" aria-label="PubMed reference 181">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhs1GmtbjJ" aria-label="CAS reference 181">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 181" href="http://scholar.google.com/scholar_lookup?&title=Presence%20of%20genetic%20variants%20among%20young%20men%20with%20severe%20COVID-19&journal=JAMA&doi=10.1001%2Fjama.2020.13719&volume=324&pages=663-673&publication_year=2020&author=Made%2CCI"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="182."><p class="c-article-references__text" id="ref-CR182">Fallerini, C. et al. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study. <i>Elife</i> <b>10</b>, e67569 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7554/eLife.67569" data-track-item_id="10.7554/eLife.67569" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7554%2FeLife.67569" aria-label="Article reference 182" data-doi="10.7554/eLife.67569">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33650967" aria-label="PubMed reference 182">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987337" aria-label="PubMed Central reference 182">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 182" href="http://scholar.google.com/scholar_lookup?&title=Association%20of%20Toll-like%20receptor%207%20variants%20with%20life-threatening%20COVID-19%20disease%20in%20males%3A%20findings%20from%20a%20nested%20case-control%20study&journal=Elife&doi=10.7554%2FeLife.67569&volume=10&publication_year=2021&author=Fallerini%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="183."><p class="c-article-references__text" id="ref-CR183">Ghafouri-Fard, S. et al. Effects of host genetic variations on response to, susceptibility and severity of respiratory infections. <i>Biomed. Pharmacother.</i> <b>128</b>, 110296 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.biopha.2020.110296" data-track-item_id="10.1016/j.biopha.2020.110296" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.biopha.2020.110296" aria-label="Article reference 183" data-doi="10.1016/j.biopha.2020.110296">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtVKmt7rE" aria-label="CAS reference 183">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32480226" aria-label="PubMed reference 183">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7258806" aria-label="PubMed Central reference 183">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 183" href="http://scholar.google.com/scholar_lookup?&title=Effects%20of%20host%20genetic%20variations%20on%20response%20to%2C%20susceptibility%20and%20severity%20of%20respiratory%20infections&journal=Biomed.%20Pharmacother.&doi=10.1016%2Fj.biopha.2020.110296&volume=128&publication_year=2020&author=Ghafouri-Fard%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="184."><p class="c-article-references__text" id="ref-CR184">Darbani, B. The expression and polymorphism of entry machinery for COVID-19 in human: juxtaposing population groups, gender, and different tissues. <i>Int. J. Environ. Res. Public Health</i> <b>17</b>, 3433 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3390/ijerph17103433" data-track-item_id="10.3390/ijerph17103433" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3390%2Fijerph17103433" aria-label="Article reference 184" data-doi="10.3390/ijerph17103433">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhvVKqurzL" aria-label="CAS reference 184">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277542" aria-label="PubMed Central reference 184">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 184" href="http://scholar.google.com/scholar_lookup?&title=The%20expression%20and%20polymorphism%20of%20entry%20machinery%20for%20COVID-19%20in%20human%3A%20juxtaposing%20population%20groups%2C%20gender%2C%20and%20different%20tissues&journal=Int.%20J.%20Environ.%20Res.%20Public%20Health&doi=10.3390%2Fijerph17103433&volume=17&publication_year=2020&author=Darbani%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="185."><p class="c-article-references__text" id="ref-CR185">Devaux, C. A., Rolain, J. M. & Raoult, D. ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. <i>J. Microbiol. Immunol. Infect.</i> <b>53</b>, 425–435 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jmii.2020.04.015" data-track-item_id="10.1016/j.jmii.2020.04.015" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jmii.2020.04.015" aria-label="Article reference 185" data-doi="10.1016/j.jmii.2020.04.015">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXovFKms78%3D" aria-label="CAS reference 185">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32414646" aria-label="PubMed reference 185">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201239" aria-label="PubMed Central reference 185">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 185" href="http://scholar.google.com/scholar_lookup?&title=ACE2%20receptor%20polymorphism%3A%20susceptibility%20to%20SARS-CoV-2%2C%20hypertension%2C%20multi-organ%20failure%2C%20and%20COVID-19%20disease%20outcome&journal=J.%20Microbiol.%20Immunol.%20Infect.&doi=10.1016%2Fj.jmii.2020.04.015&volume=53&pages=425-435&publication_year=2020&author=Devaux%2CCA&author=Rolain%2CJM&author=Raoult%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="186."><p class="c-article-references__text" id="ref-CR186">Tipnis, S. R. et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. <i>J. Biol. Chem.</i> <b>275</b>, 33238–33243 (2000).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1074/jbc.M002615200" data-track-item_id="10.1074/jbc.M002615200" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1074%2Fjbc.M002615200" aria-label="Article reference 186" data-doi="10.1074/jbc.M002615200">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3cXnvVOqtbw%3D" aria-label="CAS reference 186">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10924499" aria-label="PubMed reference 186">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 186" href="http://scholar.google.com/scholar_lookup?&title=A%20human%20homolog%20of%20angiotensin-converting%20enzyme.%20Cloning%20and%20functional%20expression%20as%20a%20captopril-insensitive%20carboxypeptidase&journal=J.%20Biol.%20Chem.&doi=10.1074%2Fjbc.M002615200&volume=275&pages=33238-33243&publication_year=2000&author=Tipnis%2CSR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="187."><p class="c-article-references__text" id="ref-CR187">Yan, R. et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. <i>Science</i> <b>367</b>, 1444–1448 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1126/science.abb2762" data-track-item_id="10.1126/science.abb2762" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1126%2Fscience.abb2762" aria-label="Article reference 187" data-doi="10.1126/science.abb2762">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXlslymsLo%3D" aria-label="CAS reference 187">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32132184" aria-label="PubMed reference 187">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164635" aria-label="PubMed Central reference 187">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 187" href="http://scholar.google.com/scholar_lookup?&title=Structural%20basis%20for%20the%20recognition%20of%20SARS-CoV-2%20by%20full-length%20human%20ACE2&journal=Science&doi=10.1126%2Fscience.abb2762&volume=367&pages=1444-1448&publication_year=2020&author=Yan%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="188."><p class="c-article-references__text" id="ref-CR188">Cao, Y. et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. <i>Cell Discov.</i> <b>6</b>, 11 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41421-020-0147-1" data-track-item_id="10.1038/s41421-020-0147-1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41421-020-0147-1" aria-label="Article reference 188" data-doi="10.1038/s41421-020-0147-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXktlGhtrY%3D" aria-label="CAS reference 188">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32133153" aria-label="PubMed reference 188">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040011" aria-label="PubMed Central reference 188">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 188" href="http://scholar.google.com/scholar_lookup?&title=Comparative%20genetic%20analysis%20of%20the%20novel%20coronavirus%20%282019-nCoV%2FSARS-CoV-2%29%20receptor%20ACE2%20in%20different%20populations&journal=Cell%20Discov.&doi=10.1038%2Fs41421-020-0147-1&volume=6&publication_year=2020&author=Cao%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="189."><p class="c-article-references__text" id="ref-CR189">Mariappan, V., Rao, S. R. & Balakrishna Pillai, A. Angiotensin-converting enzyme 2: a protective factor in regulating disease virulence of SARS-COV-2. <i>IUBMB Life</i> <b>72</b>, 2533–2545 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/iub.2391" data-track-item_id="10.1002/iub.2391" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fiub.2391" aria-label="Article reference 189" data-doi="10.1002/iub.2391">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitVWjsbbF" aria-label="CAS reference 189">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33031602" aria-label="PubMed reference 189">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 189" href="http://scholar.google.com/scholar_lookup?&title=Angiotensin-converting%20enzyme%202%3A%20a%20protective%20factor%20in%20regulating%20disease%20virulence%20of%20SARS-COV-2&journal=IUBMB%20Life&doi=10.1002%2Fiub.2391&volume=72&pages=2533-2545&publication_year=2020&author=Mariappan%2CV&author=Rao%2CSR&author=Balakrishna%20Pillai%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="190."><p class="c-article-references__text" id="ref-CR190">Iyer, G. R. et al. Infectivity and progression of COVID-19 based on selected host candidate gene variants. <i>Front. Genet.</i> <b>11</b>, 861 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fgene.2020.00861" data-track-item_id="10.3389/fgene.2020.00861" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffgene.2020.00861" aria-label="Article reference 190" data-doi="10.3389/fgene.2020.00861">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1GisrbJ" aria-label="CAS reference 190">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33101356" aria-label="PubMed reference 190">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500201" aria-label="PubMed Central reference 190">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 190" href="http://scholar.google.com/scholar_lookup?&title=Infectivity%20and%20progression%20of%20COVID-19%20based%20on%20selected%20host%20candidate%20gene%20variants&journal=Front.%20Genet.&doi=10.3389%2Ffgene.2020.00861&volume=11&publication_year=2020&author=Iyer%2CGR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="191."><p class="c-article-references__text" id="ref-CR191">Wu, Y. H., Li, J. Y., Wang, C., Zhang, L. M. & Qiao, H. The ACE2 G8790A polymorphism: involvement in type 2 diabetes mellitus combined with cerebral stroke. <i>J. Clin. Lab. Anal.</i> <b>31</b>, e22033 (2017).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/jcla.22033" data-track-item_id="10.1002/jcla.22033" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fjcla.22033" aria-label="Article reference 191" data-doi="10.1002/jcla.22033">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2sXksF2ku78%3D" aria-label="CAS reference 191">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 191" href="http://scholar.google.com/scholar_lookup?&title=The%20ACE2%20G8790A%20polymorphism%3A%20involvement%20in%20type%202%20diabetes%20mellitus%20combined%20with%20cerebral%20stroke&journal=J.%20Clin.%20Lab.%20Anal.&doi=10.1002%2Fjcla.22033&volume=31&publication_year=2017&author=Wu%2CYH&author=Li%2CJY&author=Wang%2CC&author=Zhang%2CLM&author=Qiao%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="192."><p class="c-article-references__text" id="ref-CR192">Asselta, R., Paraboschi, E. M., Mantovani, A. & Duga, S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. <i>Aging</i> <b>12</b>, 10087–10098 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.18632/aging.103415" data-track-item_id="10.18632/aging.103415" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.18632%2Faging.103415" aria-label="Article reference 192" data-doi="10.18632/aging.103415">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXisFCmt7nJ" aria-label="CAS reference 192">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32501810" aria-label="PubMed reference 192">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346072" aria-label="PubMed Central reference 192">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 192" href="http://scholar.google.com/scholar_lookup?&title=ACE2%20and%20TMPRSS2%20variants%20and%20expression%20as%20candidates%20to%20sex%20and%20country%20differences%20in%20COVID-19%20severity%20in%20Italy&journal=Aging&doi=10.18632%2Faging.103415&volume=12&pages=10087-10098&publication_year=2020&author=Asselta%2CR&author=Paraboschi%2CEM&author=Mantovani%2CA&author=Duga%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="193."><p class="c-article-references__text" id="ref-CR193">Srivastava, A. et al. Genetic association of ACE2 rs2285666 polymorphism with COVID-19 spatial distribution in India. <i>Front. Genet.</i> <b>11</b>, 564741 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fgene.2020.564741" data-track-item_id="10.3389/fgene.2020.564741" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffgene.2020.564741" aria-label="Article reference 193" data-doi="10.3389/fgene.2020.564741">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis1Gis77O" aria-label="CAS reference 193">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33101387" aria-label="PubMed reference 193">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545580" aria-label="PubMed Central reference 193">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 193" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20association%20of%20ACE2%20rs2285666%20polymorphism%20with%20COVID-19%20spatial%20distribution%20in%20India&journal=Front.%20Genet.&doi=10.3389%2Ffgene.2020.564741&volume=11&publication_year=2020&author=Srivastava%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="194."><p class="c-article-references__text" id="ref-CR194">Li, Q., Cao, Z. & Rahman, P. Genetic variability of human angiotensin-converting enzyme 2 (hACE2) among various ethnic populations. <i>Mol. Genet. Genom. Med.</i> <b>8</b>, e1344 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhs1KiurfO" aria-label="CAS reference 194">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 194" href="http://scholar.google.com/scholar_lookup?&title=Genetic%20variability%20of%20human%20angiotensin-converting%20enzyme%202%20%28hACE2%29%20among%20various%20ethnic%20populations&journal=Mol.%20Genet.%20Genom.%20Med.&volume=8&publication_year=2020&author=Li%2CQ&author=Cao%2CZ&author=Rahman%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="195."><p class="c-article-references__text" id="ref-CR195">Lippi, G., Lavie, C. J., Henry, B. M. & Sanchis-Gomar, F. Do genetic polymorphisms in angiotensin converting enzyme 2 (ACE2) gene play a role in coronavirus disease 2019 (COVID-19)? <i>Clin. Chem. Lab. Med.</i> <b>58</b>, 1415–1422 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1515/cclm-2020-0727" data-track-item_id="10.1515/cclm-2020-0727" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1515%2Fcclm-2020-0727" aria-label="Article reference 195" data-doi="10.1515/cclm-2020-0727">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhvVGiurzF" aria-label="CAS reference 195">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32598305" aria-label="PubMed reference 195">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 195" href="http://scholar.google.com/scholar_lookup?&title=Do%20genetic%20polymorphisms%20in%20angiotensin%20converting%20enzyme%202%20%28ACE2%29%20gene%20play%20a%20role%20in%20coronavirus%20disease%202019%20%28COVID-19%29%3F&journal=Clin.%20Chem.%20Lab.%20Med.&doi=10.1515%2Fcclm-2020-0727&volume=58&pages=1415-1422&publication_year=2020&author=Lippi%2CG&author=Lavie%2CCJ&author=Henry%2CBM&author=Sanchis-Gomar%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="196."><p class="c-article-references__text" id="ref-CR196">Hussain, M. et al. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. <i>J. Med. Virol.</i> <b>92</b>, 1580–1586 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/jmv.25832" data-track-item_id="10.1002/jmv.25832" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fjmv.25832" aria-label="Article reference 196" data-doi="10.1002/jmv.25832">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXntFygsLc%3D" aria-label="CAS reference 196">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32249956" aria-label="PubMed reference 196">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 196" href="http://scholar.google.com/scholar_lookup?&title=Structural%20variations%20in%20human%20ACE2%20may%20influence%20its%20binding%20with%20SARS-CoV-2%20spike%20protein&journal=J.%20Med.%20Virol.&doi=10.1002%2Fjmv.25832&volume=92&pages=1580-1586&publication_year=2020&author=Hussain%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="197."><p class="c-article-references__text" id="ref-CR197">Benetti, E. et al. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population. <i>Eur. J. Hum. Genet.</i> <b>28</b>, 1602–1614 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41431-020-0691-z" data-track-item_id="10.1038/s41431-020-0691-z" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41431-020-0691-z" aria-label="Article reference 197" data-doi="10.1038/s41431-020-0691-z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhsVWhtL3J" aria-label="CAS reference 197">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32681121" aria-label="PubMed reference 197">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366459" aria-label="PubMed Central reference 197">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 197" href="http://scholar.google.com/scholar_lookup?&title=ACE2%20gene%20variants%20may%20underlie%20interindividual%20variability%20and%20susceptibility%20to%20COVID-19%20in%20the%20Italian%20population&journal=Eur.%20J.%20Hum.%20Genet.&doi=10.1038%2Fs41431-020-0691-z&volume=28&pages=1602-1614&publication_year=2020&author=Benetti%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="198."><p class="c-article-references__text" id="ref-CR198">Chen, J. et al. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. <i>Aging Cell</i> <b>19</b>, e13168 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/acel.13168" data-track-item_id="10.1111/acel.13168" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Facel.13168" aria-label="Article reference 198" data-doi="10.1111/acel.13168">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323071" aria-label="PubMed Central reference 198">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 198" href="http://scholar.google.com/scholar_lookup?&title=Individual%20variation%20of%20the%20SARS-CoV-2%20receptor%20ACE2%20gene%20expression%20and%20regulation&journal=Aging%20Cell&doi=10.1111%2Facel.13168&volume=19&publication_year=2020&author=Chen%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="199."><p class="c-article-references__text" id="ref-CR199">Heinzelman, P. & Romero, P. A. Discovery of human ACE2 variants with altered recognition by the SARS-CoV-2 spike protein. <i>PLoS One</i> <b>16</b>, e0251585 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1371/journal.pone.0251585" data-track-item_id="10.1371/journal.pone.0251585" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1371%2Fjournal.pone.0251585" aria-label="Article reference 199" data-doi="10.1371/journal.pone.0251585">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhtFSrtbbF" aria-label="CAS reference 199">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33979391" aria-label="PubMed reference 199">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115845" aria-label="PubMed Central reference 199">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 199" href="http://scholar.google.com/scholar_lookup?&title=Discovery%20of%20human%20ACE2%20variants%20with%20altered%20recognition%20by%20the%20SARS-CoV-2%20spike%20protein&journal=PLoS%20One&doi=10.1371%2Fjournal.pone.0251585&volume=16&publication_year=2021&author=Heinzelman%2CP&author=Romero%2CPA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="200."><p class="c-article-references__text" id="ref-CR200">McCoy, J. et al. Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are anti-androgens a potential treatment for COVID-19? <i>J. Cosmet. Dermatol.</i> <b>19</b>, 1542–1543 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/jocd.13455" data-track-item_id="10.1111/jocd.13455" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fjocd.13455" aria-label="Article reference 200" data-doi="10.1111/jocd.13455">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32333494" aria-label="PubMed reference 200">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 200" href="http://scholar.google.com/scholar_lookup?&title=Racial%20variations%20in%20COVID-19%20deaths%20may%20be%20due%20to%20androgen%20receptor%20genetic%20variants%20associated%20with%20prostate%20cancer%20and%20androgenetic%20alopecia.%20Are%20anti-androgens%20a%20potential%20treatment%20for%20COVID-19%3F&journal=J.%20Cosmet.%20Dermatol.&doi=10.1111%2Fjocd.13455&volume=19&pages=1542-1543&publication_year=2020&author=McCoy%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="201."><p class="c-article-references__text" id="ref-CR201">Carethers, J. M. Insights into disparities observed with COVID-19. <i>J. Intern. Med.</i> <b>289</b>, 463–473 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/joim.13199" data-track-item_id="10.1111/joim.13199" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fjoim.13199" aria-label="Article reference 201" data-doi="10.1111/joim.13199">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33164230" aria-label="PubMed reference 201">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXnt1arsbk%3D" aria-label="CAS reference 201">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 201" href="http://scholar.google.com/scholar_lookup?&title=Insights%20into%20disparities%20observed%20with%20COVID-19&journal=J.%20Intern.%20Med.&doi=10.1111%2Fjoim.13199&volume=289&pages=463-473&publication_year=2020&author=Carethers%2CJM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="202."><p class="c-article-references__text" id="ref-CR202">Wambier, C. G. et al. Androgen sensitivity gateway to COVID-19 disease severity. <i>Drug Dev. Res.</i> <b>81</b>, 771–776 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/ddr.21688" data-track-item_id="10.1002/ddr.21688" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fddr.21688" aria-label="Article reference 202" data-doi="10.1002/ddr.21688">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXptlerur4%3D" aria-label="CAS reference 202">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32412125" aria-label="PubMed reference 202">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 202" href="http://scholar.google.com/scholar_lookup?&title=Androgen%20sensitivity%20gateway%20to%20COVID-19%20disease%20severity&journal=Drug%20Dev.%20Res.&doi=10.1002%2Fddr.21688&volume=81&pages=771-776&publication_year=2020&author=Wambier%2CCG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="203."><p class="c-article-references__text" id="ref-CR203">Mjaess, G., Karam, A., Aoun, F., Albisinni, S. & Roumeguère, T. COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor. <i>Prog. Urol.</i> <b>30</b>, 484–487 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.purol.2020.05.007" data-track-item_id="10.1016/j.purol.2020.05.007" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.purol.2020.05.007" aria-label="Article reference 203" data-doi="10.1016/j.purol.2020.05.007">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DC%2BB38notVKrtQ%3D%3D" aria-label="CAS reference 203">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32620366" aria-label="PubMed reference 203">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242948" aria-label="PubMed Central reference 203">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 203" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%20and%20the%20male%20susceptibility%3A%20the%20role%20of%20ACE2%2C%20TMPRSS2%20and%20the%20androgen%20receptor&journal=Prog.%20Urol.&doi=10.1016%2Fj.purol.2020.05.007&volume=30&pages=484-487&publication_year=2020&author=Mjaess%2CG&author=Karam%2CA&author=Aoun%2CF&author=Albisinni%2CS&author=Roumegu%C3%A8re%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="204."><p class="c-article-references__text" id="ref-CR204">Sironi, M. et al. SARS-CoV-2 and COVID-19: a genetic, epidemiological, and evolutionary perspective. <i>Infect. Genet. Evol.</i> <b>84</b>, 104384 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.meegid.2020.104384" data-track-item_id="10.1016/j.meegid.2020.104384" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.meegid.2020.104384" aria-label="Article reference 204" data-doi="10.1016/j.meegid.2020.104384">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtVOju73K" aria-label="CAS reference 204">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32473976" aria-label="PubMed reference 204">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256558" aria-label="PubMed Central reference 204">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 204" href="http://scholar.google.com/scholar_lookup?&title=SARS-CoV-2%20and%20COVID-19%3A%20a%20genetic%2C%20epidemiological%2C%20and%20evolutionary%20perspective&journal=Infect.%20Genet.%20Evol.&doi=10.1016%2Fj.meegid.2020.104384&volume=84&publication_year=2020&author=Sironi%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="205."><p class="c-article-references__text" id="ref-CR205">COVID-19 Host Genetics Initiative. The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic. <i>Eur. J. Hum. Genet</i>. <b>28</b>, 715–718 (2020).</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="206."><p class="c-article-references__text" id="ref-CR206">Asselah, T., Durantel, D., Pasmant, E., Lau, G. & Schinazi, R. F. COVID-19: discovery, diagnostics and drug development. <i>J. Hepatol.</i> <b>74</b>, 168–184 (2021).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jhep.2020.09.031" data-track-item_id="10.1016/j.jhep.2020.09.031" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jhep.2020.09.031" aria-label="Article reference 206" data-doi="10.1016/j.jhep.2020.09.031">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXit12iur7K" aria-label="CAS reference 206">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33038433" aria-label="PubMed reference 206">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 206" href="http://scholar.google.com/scholar_lookup?&title=COVID-19%3A%20discovery%2C%20diagnostics%20and%20drug%20development&journal=J.%20Hepatol.&doi=10.1016%2Fj.jhep.2020.09.031&volume=74&pages=168-184&publication_year=2021&author=Asselah%2CT&author=Durantel%2CD&author=Pasmant%2CE&author=Lau%2CG&author=Schinazi%2CRF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="207."><p class="c-article-references__text" id="ref-CR207">Milne, R. Societal considerations in host genome testing for COVID-19. <i>Genet. Med.</i> <b>22</b>, 1464–1466 (2020).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41436-020-0861-y" data-track-item_id="10.1038/s41436-020-0861-y" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41436-020-0861-y" aria-label="Article reference 207" data-doi="10.1038/s41436-020-0861-y">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhtFSqu7nJ" aria-label="CAS reference 207">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32514089" aria-label="PubMed reference 207">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 207" href="http://scholar.google.com/scholar_lookup?&title=Societal%20considerations%20in%20host%20genome%20testing%20for%20COVID-19&journal=Genet.%20Med.&doi=10.1038%2Fs41436-020-0861-y&volume=22&pages=1464-1466&publication_year=2020&author=Milne%2CR"> Google Scholar</a> </p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41392-021-00736-8?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>We acknowledge all the participants of our study. This work was supported by the Special Emergency Project for Novel Coronavirus Pneumonia from the Science and Technology Department of Hunan Province (2020SK3032).</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><span class="c-article-author-information__subtitle u-visually-hidden" id="author-notes">Author notes</span><ol class="c-article-author-information__list"><li class="c-article-author-information__item" id="na1"><p>These authors contributed equally: Hao Deng, Xue Yan.</p></li></ol><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Health Management Center, the Third Xiangya Hospital, Central South University, Changsha, China</p><p class="c-article-author-affiliation__authors-list">Hao Deng, Xue Yan & Lamei Yuan</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China</p><p class="c-article-author-affiliation__authors-list">Hao Deng, Xue Yan & Lamei Yuan</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Disease Genome Research Center, Central South University, Changsha, China</p><p class="c-article-author-affiliation__authors-list">Hao Deng, Xue Yan & Lamei Yuan</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China</p><p class="c-article-author-affiliation__authors-list">Hao Deng & Lamei Yuan</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Hao-Deng-Aff1-Aff2-Aff3-Aff4"><span class="c-article-authors-search__title u-h3 js-search-name">Hao Deng</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Hao%20Deng" class="c-article-button" data-track="click" data-track-action="author link - 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H.D. and L.Y. contributed to reviewing and editing the manuscript before submission. All authors read and approved the final manuscript.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:hdeng008@yahoo.com">Hao Deng</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading" id="FPar1">Competing interests</h3> <p>The authors declare no competing interests.</p> </div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec26-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec26">Supplementary information</h2><div class="c-article-section__content" id="Sec26-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM1"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="supplementary materials" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41392-021-00736-8/MediaObjects/41392_2021_736_MOESM1_ESM.pdf" data-supp-info-image="">Supplementary materials</a></h3></div></div></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"> <p><b>Open Access</b> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Deng, H., Yan, X. & Yuan, L. Human genetic basis of coronavirus disease 2019. <i>Sig Transduct Target Ther</i> <b>6</b>, 344 (2021). https://doi.org/10.1038/s41392-021-00736-8</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/s41392-021-00736-8?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2021-04-11">11 April 2021</time></span></p></li><li 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