An African ancestry-specific nonsense variant in CD36 is associated with a higher risk of dilated cardiomyopathy
Jennifer E. Huffman, Liam Gaziano, Zeina R. Al Sayed, Renae Judy, Laura M. Raffield, Kiran J. Biddinger, Brian Charest, Anant Chopra, David Gagnon, Xiuqing Guo, Vera V. Koledova, Michael G. Levin, Yuan‐I Min, James P. Pirruccello, Nosheen Reza, Richard Ruan, Shefali S. Verma, Bharath Ambale‐Venkatesh, Anurag Verma, Jie Yao, J. Jeffrey Carr, Juan P. Casas, Kelly Cho, João A.C. Lima, Wendy S. Post, Daniel J. Rader, Marylyn D. Ritchie, Amil M. 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, VA Million Veteran Program, Sumitra Muralidhar, Jennifer Moser, Jennifer E. Deen, Philip S. Tsao, Elizabeth R. Hauser, Amy Kilborne, Michael E. Matheny, Dave Oslin, Jessica V. Brewer, Mary T. Brophy, Lori Churby, Scott L. DuVall, Saiju Pyarajan, Robert Ringer, Luis E. Silva, Shahpoor Shayan, Brady Stephens, Stacey B. Whitbourne, Themistocles L. Assimes, Adriana M. Hung, Henry R. Kranzler, Yan V. Sun, Patrick T. Ellinor, Jacob Joseph, Krishna G. Aragam
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.