A Common CD36 Variant and the Genetic Landscape of Dilated Cardiomyopathy in Individuals of African Ancestry

Importance 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 TTN , which encodes the sarcomeric protein titin, are the most common established monogenic cause of DCM. A common CD36 nonsense variant enriched among individuals of African ancestry has also been shown to account for a substantial burden of DCM. Objective To compare the contribution of a CD36 nonsense variant to DCM risk with that of truncating variants in TTN and pathogenic or likely pathogenic variants in other established genes for DCM. Design, Setting, and Participants 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). Exposure Carrier status for TTN truncating variants, pathogenic or likely pathogenic variants in 11 high-confidence genes for DCM, and the nonsense variant CD36 Y325* (0, 1, or 2 copies). Main Outcomes and Measures Risk of DCM, prevalence of variant carriers among DCM cases, and population attributable fraction of DCM. Results Among 82 623 individuals of predominantly African ancestry across 4 cohorts, the mean age was 53.4 years (SD, 13.9 years), 47 124 were male, and 1316 had DCM. Individuals who were homozygous for the CD36 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). TTN 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 CD36 , 56 (4.3%) had TTN 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 CD36 Y325* carriers, the population attributable fraction for CD36 (9.0% [6.2% for heterozygous carriers and 2.8% for homozygous carriers]) surpassed the population attributable fraction for TTN truncating variants (3.7%). Conclusions and Relevance In 4 US cohorts, an ancestry-specific CD36 variant contributed more to DCM burden among individuals of African ancestry than established genes for DCM, including TTN 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.