An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy

The high burden of dilated cardiomyopathy (DCM) in individuals of African descent remains incompletely explained. Here, to explore a genetic basis, we conducted a genome-wide association study in 1,802 DCM cases and 93,804 controls of African genetic ancestry (AFR). A nonsense variant ( rs3211938 :G) in CD36 was associated with increased risk of DCM. This variant, believed to be under positive selection due to a protective role in malaria resistance, is present in 17% of AFR individuals but <0.1% of European genetic ancestry (EUR) individuals. Homozygotes for the risk allele, who comprise ~1% of the AFR population, had approximately threefold higher odds of DCM. Among those without clinical cardiomyopathy, homozygotes exhibited an 8% absolute reduction in left ventricular ejection fraction. In AFR, the DCM population attributable fraction for the CD36 variant was 8.1%. This single variant accounted for approximately 20% of the excess DCM risk in individuals of AFR compared to those of EUR. Experiments in human induced pluripotent stem cell-derived cardiomyocytes demonstrated that CD36 loss of function impairs fatty acid uptake and disrupts cardiac metabolism and contractility. These findings implicate CD36 loss of function and suboptimal myocardial energetics as a prevalent cause of DCM in individuals of African descent.

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Publication Details

Journal
Nature Genetics
Published
2025-10-31
DOI
https://doi.org/10.1038/s41588-025-02372-2
Citations
2
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
3.63

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article

An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy

Peter W.F. Wilson, Luis E. Silva, J. Jeffrey Carr, Themistocles L. Assimes et al.
2 citations
Nature Genetics
Genetic Associations and Epidemiology
3.63
article

An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy

Peter W.F. Wilson, Luis E. Silva, J. Jeffrey Carr, Themistocles L. Assimes, Nosheen Reza, Liam Gaziano, Michael E. Matheny, Jennifer E. Huffman, Jessica V. Brewer, Anurag Verma, James P. Pirruccello, Brian Charest, Juan P. Casas, David Gagnon, J. Michael Gaziano, Scott L. DuVall, Amil M. Shah, Anant Chopra, João A.C. Lima, Yan V. Sun, Jerome I. Rotter, Renae Judy, Laura M. Raffield, Krishna G. Aragam, Richard Ruan, Sumitra Muralidhar, Wendy S. Post, Kelly Cho, Jacob Joseph, Jennifer E. Deen, James Greg Terry, Shahpoor Alex Shayan, Saiju Pyarajan, Adriana M. Hung, Philip S. Tsao, Brady M. Stephens, Elizabeth R. Hauser, Bharath Ambale‐Venkatesh, Zeina R. Al Sayed, Lawrence S. Phillips, Daniel James Rader, Patrick T. Ellinor, Stephen S. Rich, Vera V. Koledova, Henry R. Kranzler, Jennifer Moser, Lori Churby, Stacey B. Whitbourne, Mary T. Brophy, Michael G. Levin, Shefali S. Verma, Scott M. Damrauer, Christopher J. O’Donnell, Kiran J. Biddinger, Kathryn L. Lunetta, Yuan‐I Min, Xiuqing Guo, Robert J. Ringer, Marylyn D. Ritchie, Kent D. Taylor, Jie Yao, Dave Oslin, Amy Kilborne
article en
2 citations

Abstract

The high burden of dilated cardiomyopathy (DCM) in individuals of African descent remains incompletely explained. Here, to explore a genetic basis, we conducted a genome-wide association study in 1,802 DCM cases and 93,804 controls of African genetic ancestry (AFR). A nonsense variant ( rs3211938 :G) in CD36 was associated with increased risk of DCM. This variant, believed to be under positive selection due to a protective role in malaria resistance, is present in 17% of AFR individuals but <0.1% of European genetic ancestry (EUR) individuals. Homozygotes for the risk allele, who comprise ~1% of the AFR population, had approximately threefold higher odds of DCM. Among those without clinical cardiomyopathy, homozygotes exhibited an 8% absolute reduction in left ventricular ejection fraction. In AFR, the DCM population attributable fraction for the CD36 variant was 8.1%. This single variant accounted for approximately 20% of the excess DCM risk in individuals of AFR compared to those of EUR. Experiments in human induced pluripotent stem cell-derived cardiomyocytes demonstrated that CD36 loss of function impairs fatty acid uptake and disrupts cardiac metabolism and contractility. These findings implicate CD36 loss of function and suboptimal myocardial energetics as a prevalent cause of DCM in individuals of African descent.

Nature GeneticsVol. 57(11)
Broad Institute (US), Boston University (US), University of North Carolina at Chapel Hill (US), Brigham and Women's Hospital (US), Cleveland Clinic (US), United States Department of Veterans Affairs (US), Johns Hopkins University (US), Emory University (US), Bayer (United States) (US), University of California, San Francisco (US), VA Palo Alto Health Care System (US), Brown University (US), UCLA Medical Center (US), VA Boston Healthcare System (US), Providence VA Medical Center (US), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), Massachusetts General Hospital (US), Health Services Research & Development (US), VA Salt Lake City Healthcare System (US), Canandaigua VA Medical Center (US), VA Tennessee Valley Healthcare System (US), Novartis (United States) (US), Ann Arbor VA Medical Center (US), Philadelphia VA Medical Center (US), Durham VA Medical Center (US), Atlanta VA Medical Center (US), New Mexico VA Health Care System (US), Harbor–UCLA Medical Center (US), University of Virginia (US), University of Pennsylvania (US), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US)
U.S. Department of Health and Human Services, U.S. Department of Veterans Affairs, American Heart Association, Office of Research and Development, Broad Institute, National Institutes of Health, National Heart, Lung, and Blood Institute
Openalex Percentile: Top 6%
Genetic Associations and Epidemiology
3.63
DOIOpen Access PDFOpenAlex
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