{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:40:28Z","timestamp":1792424428094,"version":"4.5.0"},"reference-count":28,"publisher":"American Medical Association (AMA)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"abstract":"\n Importance<\/jats:title>\n \n Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of predominantly African ancestry, among whom familial clustering of disease is more pronounced relative to those of predominantly European ancestry. Truncating variants in\n TTN<\/jats:italic>\n , which encodes the sarcomeric protein titin, are the most common established monogenic cause of DCM. A common\n CD36<\/jats:italic>\n nonsense variant enriched among individuals of African ancestry has also been shown to account for a substantial burden of DCM.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To compare the contribution of a\n CD36<\/jats:italic>\n nonsense variant to DCM risk with that of truncating variants in\n TTN<\/jats:italic>\n and pathogenic or likely pathogenic variants in other established genes for DCM.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n Multicohort genetic association study including participants of African and European ancestry with exome or genome sequence data and DCM case status from the following 4 US datasets: All of Us Research Program (recruitment: 2017-present; last follow-up: August 27, 2024), Million Veteran Program (recruitment: 2011-present; last follow-up: September 30, 2024), Penn Medicine Biobank (recruitment: 2013-present; last follow-up: November 14, 2022), and the DCM Precision Medicine Study (recruitment: 2016-2020; last follow-up: March 15, 2020).<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n \n Carrier status for\n TTN<\/jats:italic>\n truncating variants, pathogenic or likely pathogenic variants in 11 high-confidence genes for DCM, and the nonsense variant\n CD36<\/jats:italic>\n Y325* (0, 1, or 2 copies).\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Risk of DCM, prevalence of variant carriers among DCM cases, and population attributable fraction of DCM.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 82\u202f623 individuals of predominantly African ancestry across 4 cohorts, the mean age was 53.4 years (SD, 13.9 years), 47\u202f124 were male, and 1316 had DCM. Individuals who were homozygous for the\n CD36<\/jats:italic>\n Y325* risk allele had a higher risk of DCM (odds ratio [OR], 4.8; 95% CI, 3.1-7.3) as did those who were heterozygous (OR, 1.4; 95% CI, 1.2-1.7).\n TTN<\/jats:italic>\n truncating variants also conferred an elevated risk of DCM in participants of African ancestry (OR, 8.5; 95% CI, 5.5-13.0). Among 1316 individuals of African ancestry classified as DCM cases, 33 (2.5%) were homozygous for\n CD36<\/jats:italic>\n , 56 (4.3%) had\n TTN<\/jats:italic>\n truncating variants, and 16 (1.2%) had pathogenic or likely pathogenic variants in other high-confidence genes for DCM. In population-level analyses incorporating both heterozygous and homozygous\n CD36<\/jats:italic>\n Y325* carriers, the population attributable fraction for\n CD36<\/jats:italic>\n (9.0% [6.2% for heterozygous carriers and 2.8% for homozygous carriers]) surpassed the population attributable fraction for\n TTN<\/jats:italic>\n truncating variants (3.7%).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In 4 US cohorts, an ancestry-specific\n CD36<\/jats:italic>\n variant contributed more to DCM burden among individuals of African ancestry than established genes for DCM, including\n TTN<\/jats:italic>\n truncating variants that are typically considered the most common genetic cause. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2026.18449","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:00:16Z","timestamp":1792422016000},"source":"Crossref","is-referenced-by-count":0,"title":["A Common\n CD36<\/i>\n Variant and the Genetic Landscape of Dilated Cardiomyopathy in Individuals of African Ancestry"],"prefix":"10.1001","author":[{"given":"Saketh P.","family":"Challa","sequence":"first","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"},{"name":"Massachusetts Veterans Epidemiology Research and Information Collaborative, VA Boston Healthcare System, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran J.","family":"Biddinger","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"},{"name":"Massachusetts Veterans Epidemiology Research and Information Collaborative, VA Boston Healthcare System, Boston, Massachusetts"},{"name":"Department of Biomedical Informatics, Harvard University, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Abramowitz","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia"},{"name":"Donald and Barbara Zucker School of Medicine, Hofstra University and Northwell Health, Hempstead, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Zheng","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan O.","family":"Mead","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus"},{"name":"Davis Heart and Lung Research Institute, Ohio State University, Columbus"},{"name":"Ohio Colleges of Medicine Government Resource Center, Ohio State University, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renae L.","family":"Judy","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia"},{"name":"Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean J.","family":"Jurgens","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"},{"name":"Department of Experimental Cardiology, Amsterdam Cardiovascular Sciences, Heart Failure, and Arrhythmias, University of Amsterdam, Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liam","family":"Gaziano","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"},{"name":"Massachusetts Veterans Epidemiology Research and Information Collaborative, VA Boston Healthcare System, Boston, Massachusetts"},{"name":"Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Hoan","family":"Choi","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Department of Biostatistics, Boston University, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Halford","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Jordan","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus"},{"name":"Davis Heart and Lung Research Institute, Ohio State University, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Liu","sequence":"additional","affiliation":[{"name":"Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyong-Mi","family":"Chang","sequence":"additional","affiliation":[{"name":"Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania"},{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Vest","sequence":"additional","affiliation":[{"name":"Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. H. Wilson","family":"Tang","sequence":"additional","affiliation":[{"name":"Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Tsao","sequence":"additional","affiliation":[{"name":"Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, California"},{"name":"Department of Medicine, Stanford University, Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel D.","family":"Kinnamon","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus"},{"name":"Davis Heart and Lung Research Institute, Ohio State University, Columbus"},{"name":"Abbott Nutrition Research and Development, Columbus, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Damrauer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia"},{"name":"Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania"},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick T.","family":"Ellinor","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Heart and Vascular Institute, Mass General Brigham, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Levin","sequence":"additional","affiliation":[{"name":"Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania"},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia"},{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ray E.","family":"Hershberger","sequence":"additional","affiliation":[{"name":"Davis Heart and Lung Research Institute, Ohio State University, Columbus"},{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, Ohio State University, Columbus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E.","family":"Huffman","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Massachusetts Veterans Epidemiology Research and Information Collaborative, VA Boston Healthcare System, Boston, Massachusetts"},{"name":"Palo Alto Epidemiology Research and Information Center for Genomics, VA Palo Alto Health Care System, Palo Alto, California"},{"name":"Palo Alto Veterans Institute for Research, Palo Alto, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna G.","family":"Aragam","sequence":"additional","affiliation":[{"name":"Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts"},{"name":"Massachusetts Veterans Epidemiology Research and Information Collaborative, VA Boston Healthcare System, Boston, Massachusetts"},{"name":"Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"issue":"25","key":"joi260109r1","doi-asserted-by":"publisher","first-page":"2580","DOI":"10.1016\/j.jacc.2021.10.021","article-title":"Impact of racial and ethnic disparities on patients with dilated cardiomyopathy: JACC focus seminar 7\/9.","volume":"78","author":"Ntusi","year":"2021","journal-title":"J Am Coll Cardiol"},{"issue":"12","key":"joi260109r2","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1056\/NEJMoa0807265","article-title":"Racial differences in incident heart failure among young adults.","volume":"360","author":"Bibbins-Domingo","year":"2009","journal-title":"N Engl J Med"},{"issue":"7","key":"joi260109r3","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated cardiomyopathy: genetic determinants and mechanisms.","volume":"121","author":"McNally","year":"2017","journal-title":"Circ Res"},{"issue":"4","key":"joi260109r4","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.jacc.2021.11.024","article-title":"Race- and gender-based differences in cardiac structure and function and risk of heart failure.","volume":"79","author":"Chandra","year":"2022","journal-title":"J Am Coll Cardiol"},{"issue":"1","key":"joi260109r5","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1161\/CIRCULATIONAHA.120.053033","article-title":"Evidence-based assessment of genes in dilated cardiomyopathy.","volume":"144","author":"Jordan","year":"2021","journal-title":"Circulation"},{"issue":"5","key":"joi260109r6","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1001\/jama.2021.24674","article-title":"Prevalence and cumulative risk of familial idiopathic dilated cardiomyopathy.","volume":"327","author":"Huggins","year":"2022","journal-title":"JAMA"},{"issue":"7","key":"joi260109r7","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1056\/NEJMoa1110186","article-title":"Truncations of titin causing dilated cardiomyopathy.","volume":"366","author":"Herman","year":"2012","journal-title":"N Engl J Med"},{"issue":"5","key":"joi260109r8","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1001\/jama.2023.11970","article-title":"Genetic architecture of dilated cardiomyopathy in individuals of African and European ancestry.","volume":"330","author":"Jordan","year":"2023","journal-title":"JAMA"},{"issue":"11","key":"joi260109r9","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1038\/s41588-025-02372-2","article-title":"An African ancestry\u2013specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy.","volume":"57","author":"Huffman","year":"2025","journal-title":"Nat Genet"},{"issue":"1","key":"joi260109r10","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1146\/annurev-nutr-071812-161220","article-title":"Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism.","volume":"34","author":"Pepino","year":"2014","journal-title":"Annu Rev Nutr"},{"issue":"8003","key":"joi260109r11","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/s41586-023-06957-x","article-title":"Genomic data in the All of Us research program.","volume":"627","author":"All of Us Research Program Genomics Investigators","year":"2024","journal-title":"Nature"},{"key":"joi260109r12","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.jclinepi.2015.09.016","article-title":"Million Veteran Program: a mega-biobank to study genetic influences on health and disease.","volume":"70","author":"Gaziano","year":"2016","journal-title":"J Clin Epidemiol"},{"issue":"12","key":"joi260109r13","doi-asserted-by":"publisher","first-page":"1974","DOI":"10.3390\/jpm12121974","article-title":"The Penn Medicine BioBank: towards a genomics-enabled learning healthcare system to accelerate precision medicine in a diverse population.","volume":"12","author":"Verma","year":"2022","journal-title":"J Pers Med"},{"issue":"5","key":"joi260109r14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.121.008877","article-title":"Validating an idiopathic dilated cardiomyopathy diagnosis using cardiovascular magnetic resonance: the Dilated Cardiomyopathy Precision Medicine Study.","volume":"15","author":"Haas","year":"2022","journal-title":"Circ Heart Fail"},{"issue":"7809","key":"joi260109r15","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans.","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"issue":"9","key":"joi260109r16","doi-asserted-by":"publisher","first-page":"1811","DOI":"10.1038\/s41588-024-01894-5","article-title":"Rare coding variant analysis for human diseases across biobanks and ancestries.","volume":"56","author":"Jurgens","year":"2024","journal-title":"Nat Genet"},{"issue":"3","key":"joi260109r17","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package.","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J Stat Softw"},{"issue":"8","key":"joi260109r18","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1056\/NEJM199902253400804","article-title":"Racial differences in the outcome of left ventricular dysfunction.","volume":"340","author":"Dries","year":"1999","journal-title":"N Engl J Med"},{"issue":"2","key":"joi260109r19","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1097\/00001648-199303000-00013","article-title":"Black-White differences in idiopathic dilated cardiomyopathy: the Washington DC dilated Cardiomyopathy Study.","volume":"4","author":"Coughlin","year":"1993","journal-title":"Epidemiology"},{"issue":"37","key":"joi260109r20","doi-asserted-by":"publisher","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","article-title":"2023 ESC guidelines for the management of cardiomyopathies.","volume":"44","author":"Arbelo","year":"2023","journal-title":"Eur Heart J"},{"issue":"12","key":"joi260109r21","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1038\/s41588-024-01975-5","article-title":"Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience.","volume":"56","author":"Jurgens","year":"2024","journal-title":"Nat Genet"},{"issue":"12","key":"joi260109r22","doi-asserted-by":"publisher","first-page":"2646","DOI":"10.1038\/s41588-024-01952-y","article-title":"Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.","volume":"56","author":"Zheng","year":"2024","journal-title":"Nat Genet"},{"issue":"42","key":"joi260109r23","doi-asserted-by":"publisher","first-page":"32523","DOI":"10.1074\/jbc.M003826200","article-title":"Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice.","volume":"275","author":"Coburn","year":"2000","journal-title":"J Biol Chem"},{"issue":"5","key":"joi260109r24","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/S0022-2275(20)31637-0","article-title":"Defect in human myocardial long-chain fatty acid uptake is caused by FAT\/CD36 mutations.","volume":"42","author":"Tanaka","year":"2001","journal-title":"J Lipid Res"},{"issue":"19","key":"joi260109r25","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1161\/CIRCULATIONAHA.107.712901","article-title":"CD36 expression contributes to age-induced cardiomyopathy in mice.","volume":"116","author":"Koonen","year":"2007","journal-title":"Circulation"},{"issue":"3","key":"joi260109r26","doi-asserted-by":"publisher","first-page":"H552","DOI":"10.1152\/ajpheart.00626.2016","article-title":"Cardiomyocyte-specific ablation of CD36 accelerates the progression from compensated cardiac hypertrophy to heart failure.","volume":"312","author":"Sung","year":"2017","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"11","key":"joi260109r27","doi-asserted-by":"publisher","first-page":"1140","DOI":"10.1056\/NEJMra063052","article-title":"The failing heart\u2013an engine out of fuel.","volume":"356","author":"Neubauer","year":"2007","journal-title":"N Engl J Med"},{"issue":"25","key":"joi260109r28","doi-asserted-by":"publisher","first-page":"2598","DOI":"10.1016\/j.jacc.2025.09.1511","article-title":"Danicamtiv, a selective agonist of cardiac myosin, for dilated cardiomyopathy: a phase 2 open-label trial.","volume":"86","author":"Lakdawala","year":"2025","journal-title":"J Am Coll Cardiol"}],"container-title":["JAMA"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/articlepdf\/2855486\/jama_challa_2026_oi_260109_1791838645.17668.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T15:00:16Z","timestamp":1792422016000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jama\/fullarticle\/2855486"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,19]]},"references-count":28,"URL":"https:\/\/doi.org\/10.1001\/jama.2026.18449","relation":{},"ISSN":["0098-7484"],"issn-type":[{"value":"0098-7484","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10,19]]}}}