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.