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This study aimed to investigate whether a high-risk subgroup, individuals with elevated genetic predisposition to coronary artery disease (CAD), might derive more benefit than harm with aspirin, compared to those with lower genetic risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We performed genetic risk stratification of the Aspirin in Reducing Events in the Elderly (ASPREE) randomized controlled trial using a CAD polygenic risk score (GPSMult). For 12\u2009031 genotyped participants (5974 aspirin, 6057 placebo) overall, we stratified them by GPSMult quintiles (q1\u20135), then examined risk of CAD (composite of myocardial infarction and coronary heart disease death) and bleeding events using Cox models. During a median 4.6 years of follow-up with randomization to 100\u00a0mg\/day aspirin vs. placebo, 234 (1.9%) participants had CAD and 373 (3.1%) had bleeding events. In the overall cohort, aspirin resulted in higher bleeding risk [adjusted Hazard ratio (aHR) = 1.30 (1.06\u20131.61), P\u00a0=\u00a00.01] but no significant CAD reduction [aHR\u00a0=\u00a00.84 (0.64\u20131.09), P\u00a0=\u00a00.19]. However, among the highest quintile of polygenic risk (q5, top 20% of the GPSMult distribution), there was a 47% reduction in risk of CAD events with aspirin [aHR\u00a0=\u00a00.53 (0.31\u20130.90), P\u00a0=\u00a00.02] without increased bleeding risk [aHR\u00a0=\u00a01.05 (0.60\u20131.82), P\u00a0=\u00a00.88]. Interaction between the GPSMult and aspirin was significant for CAD (q5 vs. q1, P\u00a0=\u00a00.02) but not bleeding (P\u00a0=\u00a00.80).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The balance between net benefit and harm on aspirin in the primary prevention setting shifts favourably in individuals with an elevated genetic predisposition.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ehjcvp\/pvae085","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T15:22:06Z","timestamp":1729783326000},"page":"84-91","source":"Crossref","is-referenced-by-count":16,"title":["Polygenic risk, aspirin, and primary prevention of coronary artery 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,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniruddh P","family":"Patel","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of Harvard and MIT , Cambridge, MA 02142 ,","place":["USA"]},{"name":"Cardiology Division, Department of Medicine, Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]},{"name":"Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]},{"name":"Simches Research Center, Massachusetts General Hospital , Boston, MA 02114 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harpreet S","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego , La Jolla, CA 92093 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit V","family":"Khera","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Brigham and Women's Hospital , Boston, MA 02115 ,","place":["USA"]},{"name":"Department of Medicine, Harvard Medical School , Boston, MA 02115 ,","place":["USA"]},{"name":"Verve Therapeutics , Boston, MA 02215 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes T","family":"Neumann","sequence":"additional","affiliation":[{"name":"Sc , 553 St Kilda Road, Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"hool of Public Health and Preventive Medicine, Monash University , 553 St Kilda Road, Melbourne, VIC 3004 ,","place":["Australia"]},{"name":"Department of Cardiology, University Heart & Vascular Center (UHZ) , Hamburg 20251 ,","place":["Germany"]},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck , Hamburg 20251 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