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

CD36

Common CD36 Y325Ter nonsense variant, with higher risk in homozygotes than heterozygotes, compared with TTN truncating variants and other established dilated cardiomyopathy genes

This multicohort association study (All of Us, Million Veteran Program, Penn Medicine Biobank, DCM Precision Medicine Study) compares the contribution of the CD36 Y325Ter nonsense variant, enriched in individuals of African ancestry, with that of TTN truncating variants and pathogenic or likely pathogenic variants in 11 high-confidence dilated cardiomyopathy (DCM) genes. Among 82,623 individuals of predominantly African ancestry, 1316 of whom had DCM, DCM risk was increased in Y325Ter homozygotes (OR 4.8) and heterozygotes (OR 1.4), versus an OR of 8.5 for TTN truncating variants. Among cases, 2.5% were homozygous for the CD36 variant, 4.3% carried a TTN truncating variant and 1.2% a pathogenic or likely pathogenic variant in another established gene. The population attributable fraction of DCM for CD36 (9.0%) exceeded that of TTN truncating variants (3.7%).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An important result for interpreting exomes and genomes of patients of African ancestry with DCM: a common variant, with a modest effect in heterozygotes and a stronger one in homozygotes, weighs more at the population level than TTN. It falls outside the classic ACMG Mendelian framework, and how to report it clinically (classification, family counselling, cascade testing) remains to be defined. An attributable fraction is not individual penetrance: an OR of 1.4 in heterozygotes calls for caution before offering cardiac surveillance on this genotype alone.

Analysis by Dr Thibaut Benquey