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They verified it was associated with aortic stenosis in two independent, very large populations." /> <link rel="canonical" href="https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/" /> <meta property="og:locale" content="en_US" /> <meta property="og:type" content="article" /> <meta property="og:title" content="Novel Polygenic Risk Score Validated for Aortic Stenosis" /> <meta property="og:description" content="Researchers at Brigham and Women's Hospital developed a novel aortic stenosis polygenic risk score (PRS) that incorporates more than five million genetic variants. They verified it was associated with aortic stenosis in two independent, very large populations." /> <meta property="og:url" content="https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/" /> <meta property="og:site_name" content="Brigham On a Mission" /> <meta property="article:publisher" content="https://www.facebook.com/BrighamandWomensHospital" /> <meta property="article:published_time" content="2024-08-28T04:00:32+00:00" /> <meta property="og:image" content="https://www.brighamhealthonamission.org/wp-content/uploads/2024/08/mri-heart-or-cardiac-mri.jpg" /> <meta property="og:image:width" content="300" /> <meta property="og:image:height" content="225" /> <meta property="og:image:type" content="image/jpeg" /> <meta name="author" content="Faith Reidenbach" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:creator" content="@BrighamWomens" /> <meta name="twitter:site" content="@BrighamWomens" /> <meta name="twitter:label1" content="Written by" /> <meta name="twitter:data1" content="Faith Reidenbach" /> <meta name="twitter:label2" content="Est. reading time" /> <meta name="twitter:data2" content="3 minutes" /> <script type="application/ld+json" class="yoast-schema-graph">{"@context":"https://schema.org","@graph":[{"@type":"Article","@id":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/#article","isPartOf":{"@id":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/"},"author":{"name":"Faith Reidenbach","@id":"https://www.brighamhealthonamission.org/#/schema/person/4b9967d6f8b443d2bfc1f5771e91574c"},"headline":"Novel Polygenic Risk Score Validated for Aortic Stenosis","datePublished":"2024-08-28T04:00:32+00:00","dateModified":"2024-08-28T04:00:32+00:00","mainEntityOfPage":{"@id":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/"},"wordCount":577,"commentCount":0,"publisher":{"@id":"https://www.brighamhealthonamission.org/#organization"},"image":{"@id":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/#primaryimage"},"thumbnailUrl":"https://www.brighamhealthonamission.org/wp-content/uploads/2024/08/mri-heart-or-cardiac-mri.jpg","articleSection":["Cardiology & Heart"],"inLanguage":"en-US","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/#respond"]}]},{"@type":"WebPage","@id":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/","url":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/","name":"Novel Polygenic Risk Score Validated for Aortic Stenosis","isPartOf":{"@id":"https://www.brighamhealthonamission.org/#website"},"primaryImageOfPage":{"@id":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/#primaryimage"},"image":{"@id":"https://www.brighamhealthonamission.org/2024/08/28/novel-polygenic-risk-score-validated-for-aortic-stenosis/#primaryimage"},"thumbnailUrl":"https://www.brighamhealthonamission.org/wp-content/uploads/2024/08/mri-heart-or-cardiac-mri.jpg","datePublished":"2024-08-28T04:00:32+00:00","dateModified":"2024-08-28T04:00:32+00:00","description":"Researchers at Brigham and Women's Hospital developed a novel aortic stenosis polygenic risk score (PRS) that incorporates more than five million genetic variants. 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class="entry-title textcenter-xs">Novel Polygenic Risk Score Validated for Aortic Stenosis</h1> <div class="entry-thumbnail"> <img width="300" height="225" src="https://www.brighamhealthonamission.org/wp-content/uploads/2024/08/mri-heart-or-cardiac-mri.jpg" class="attachment-full size-full wp-post-image" alt="" decoding="async" fetchpriority="high" /> </div> </header> <div class="entry-content"> <p>Despite the high global burden of aortic stenosis, no well-established risk estimation tools are available. Moreover, many individuals have subclinical aortic valve disease (aortic sclerosis), which may not be readily captured by physical examination.</p> <p>To facilitate risk estimation, researchers at Brigham and Women’s Hospital developed a novel aortic stenosis polygenic risk score (PRS) that incorporates more than five million genetic variants. In <em><a title="Novel Polygenic Risk Score and Established Clinical Risk Factors for Risk Estimation of Aortic Stenosis" href="https://jamanetwork.com/journals/jamacardiology/article-abstract/2815695" target="_blank" rel="noopener noreferrer">JAMA Cardiology</a></em>, they verified it was associated with aortic stenosis in two independent, very large populations: aggregate data from 6 TIMI clinical trials and Veterans Affairs data from the Million Veteran Program.</p> <p>The authors are <a title="Current Cardiovascular Medicine Fellows at the Brigham" href="https://www.brighamandwomens.org/medicine/cardiovascular-medicine/cardiovascular-disease-fellowship/fellows" target="_blank" rel="noopener noreferrer">Aeron M. Small, MD, MTR</a>, a graduate of the cardiology fellowship of the <a title="The Brigham Division of Cardiovascular Medicine" href="https://www.brighamandwomens.org/medicine/cardiovascular-medicine/overview" target="_blank" rel="noopener noreferrer">Division of Cardiovascular Medicine</a> at the Brigham, <a title="Nicholas A. Marston, MD, MPH, Profile" href="https://physiciandirectory.brighamandwomens.org/details/14917/nicholas-marston-cardiovascular_medicine-boston-jamaica_plain-south_weymouth" target="_blank" rel="noopener noreferrer">Nicholas A. Marston, MD, MPH</a>, an attending physician in the Division’s <a title="The Brigham Heart and Vascular Genetics Center" href="https://www.brighamandwomens.org/heart-and-vascular-center/programs/heart-and-vascular-genetics-program" target="_blank" rel="noopener noreferrer">Heart and Vascular Genetics Center</a> and an investigator in the <a title="About the TIMI Study" href="https://timi.org/" target="_blank" rel="noopener noreferrer">Thrombolysis in Myocardial Infarction (TIMI) Study Group</a>, and colleagues.</p> <h2>Creation of a Novel Aortic Stenosis PRS</h2> <p>The researchers developed a novel PRS using data from a genome-wide association study of aortic stenosis among 287,787 white participants in the <a title="Multiancestry Genome-Wide Association Study of Aortic Stenosis Identifies Multiple Novel Loci in the Million Veteran Program" href="https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061451" target="_blank" rel="noopener noreferrer">Million Veteran Program</a> (training sample, data from 2011–2020). They chose the PRS that best estimated the risk of aortic stenosis in 479,092 UK Biobank participants of European ancestry (validation sample, data from 2006–2010).</p> <h2>Validation of the Aortic Stenosis PRS</h2> <p>The authors validated their PRS using non-overlapping data from the Million Veteran Program and aggregate data from 6 TIMI clinical trials. In analyses adjusted for age, sex, and principal components of genetic ancestry, the aortic stenosis PRS was significantly associated with aortic stenosis diagnosis among:</p> <ul> <li>141,326 white participants in the Million Veteran Program who had not been part of the training sample—OR, 1.41</li> </ul> <ul> <li>112,619 Black participants in the Million Veteran Program—OR, 1.13</li> </ul> <ul> <li>46,905 Hispanic participants in the Million Veteran Program—OR, 1.35</li> </ul> <ul> <li>59,866 individuals of European ancestry pooled from six TIMI trials—HR, 1.44</li> </ul> <h2>Aortic Stenosis PRS vs. Other Risk Predictors</h2> <p>The new PRS provided unique risk information, as it correlated weakly or not at all with established PRSs for cardiometabolic conditions. A PRS for lipoprotein(a) was the most correlated, with a modest correlation coefficient of 0.22.</p> <p>In both the Million Veteran Program and the pooled TIMI study populations, the PRS independently estimated aortic stenosis events. However, its risk discrimination ability was comparable to traditional risk factors. Age was the strongest single risk factor.</p> <p>In all age categories (<65, 65–74, and ≥75), individuals who had at least two clinical risk factors and high genetic risk (top 20<sup>th</sup> percentile) according to the PRS were at three- to four-fold increased risk of aortic stenosis diagnosis compared with individuals at low genetic risk with one or fewer clinical risk factors. The highest absolute risk difference was apparent for individuals older than 75 years (14.2% higher risk between categories versus 2.1% higher risk among individuals younger than 65 years).</p> <h2>Implications for Novel Therapies</h2> <p>This work sets the stage for refinement of an aortic stenosis PRS. For the time being, evaluation of genetic and clinical risk might be best suited to individuals in older populations where the overall prevalence of aortic stenosis is highest.</p> <p>The findings also suggest that a proportion of individuals with apparently normal lipoprotein(a) or apolipoprotein B have a residual increased genetic risk of aortic stenosis. 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