A Genome-First Study of Familial Hypercholesterolemia Comparing African and European Ancestry Individuals

Familial hypercholesterolemia (FH) is an inherited disorder characterized by lifelong elevated LDL-C (low-density lipoprotein cholesterol) and increased risk for premature myocardial infarction. FH research has focused on European populations and, consequently, estimates of global FH burden primarily reflect this ancestry, with limited data available from other groups.

We examined the prevalence and clinical outcomes of FH among 104 300 African ancestry individuals enrolled in 3 US-based cohorts: the National Institutes of Health's All of Us, Mount Sinai's BioMe, and Geisinger's MyCode. Genetic variants were evaluated according to standards provided by the Clinical Genome Resource's FH Variant Curation Expert Panel and grouped as pathogenic variants or variants of unknown significance (VUSs). Participants were assigned to European and African ancestry groups based on genetic similarity to reference populations. Clinical outcomes were LDL-C and myocardial infarction. Analyses were adjusted for age and sex. Results were meta-analyzed across cohorts.

The prevalence of a pathogenic variant was similar in the African (1 in 306) and European (1 in 273) ancestry groups. The LDL-C elevation associated with pathogenic variants was 20.81 mg/dL (95% CI, 16.17-25.45) greater in individuals with African ancestry compared with their counterparts with European ancestry. Individuals with African ancestry had 1.61 (95% CI, 1.42-1.83; P=1.2×10^-12) higher odds of having a VUS compared with individuals with European ancestry and a 10.01 mg/dL (95% CI, 6.13-13.88) greater elevation in LDL-C compared with individuals with European ancestry with a VUS. Although pathogenic variants in both ancestries conferred a 2- to 3-fold increased risk of myocardial infarction, having a VUS only conferred increased risk among the African ancestry group (odds ratio, 1.91 [95% CI, 1.18-3.10]).

The prevalence of pathogenic variants did not significantly vary between African and European ancestry groups. VUSs were both more prevalent among individuals of African ancestry and associated with an increased risk of myocardial infarction equivalent to that of a pathogenic variant. These findings suggest that dependence on existing resources for variant classification could contribute to underdiagnosis of FH in individuals of African ancestry.