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<p>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 (<a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs3211938">rs3211938</a>:G) in <i>CD36</i> 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 &lt;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 <i>CD36</i> 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 <i>CD36</i> loss of function impairs fatty acid uptake and disrupts cardiac metabolism and contractility. These findings implicate <i>CD36</i> loss of function and suboptimal myocardial energetics as a prevalent cause of DCM in individuals of African descent.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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

摘要

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.