Abstract 4139271: Investigation of familial hypercholesterolemia prevalence and association with cardiovascular disease in an African ancestry cohort.

Familial hypercholesterolemia (FH) is an inherited condition consisting of lifelong elevated LDL cholesterol levels and increased risk of cardiovascular disease. Among Western populations, the prevalence of FH has been reported to be between 1:212 to 1:331. African ancestry individuals are underrepresented in submissions to genetic resources used to determine variant pathogenicity and there are no known reports on the prevalence of FH in those populations. To create an African ancestry cohort, we performed principal component analyses on genetic data from Geisinger’s MyCode (N = 175,500) and the NIH’s All of Us (N = 98,590) cohorts to identify individuals who cluster with 1000 Genomes African superpopulation (1KG AFR). We assessed sequence variants in FH genes from our African ancestry cohort for pathogenicity using American College of Medical Genetics criteria. Lipid levels and use of lipid lowering medications were compared among those with and without a variant. Among 29,931 individuals who clustered with the 1KG AFR group, we identified 31 unique pathogenic or likely pathogenic FH variants among 108 individuals, yielding a prevalence of 1:277. Most of the pathogenic variants identified (94%) were missense variants in the LDLR gene. Mean age for individuals with a pathogenic FH variant was 40.5 years in MyCode and 50.4 years in All of Us. Of those with a pathogenic FH variant and at least one LDL measurement, we found that 52.5% had an LDL > 190mg/dl and 37.5% had an LDL > 250 mg/dl, compared to 5.7% and 0.6% of African ancestry individuals without an FH variant, respectively. The effect size of an FH variant on maximum LDL levels adjusted for age, sex, and principal components of ancestry was 90.4 mg/dL (95% CI, 69.8-111.0; p=1.1x10-17) in MyCode and 126.5 mg/dL (95% CI, 110.5-142.6, p=4.0x10-53) in All of Us. In the combined cohort, 29.6% of individuals with a pathogenic FH variant had been prescribed an LDL-lowering medication, compared to 20.9% of individuals without a variant. Overall, the prevalence of FH in an African ancestry cohort was consistent with the prevalence of FH in studies of European ancestry cohorts. The effect size of an FH variant on LDL in this cohort was large. These data suggest that African ancestry individuals with pathogenic FH variants have a high likelihood of increased LDL and concomitant cardiovascular disease risk and that there is an opportunity for additional identification and treatment of FH in this population.