Abstract Body: Background: Familial hypercholesterolemia (FH) is an inherited disorder characterized by lifelong elevated low density lipoprotein cholesterol (LDL-C). Recently, a large systematic review estimated the prevalence of FH to be 1 in 311 individuals. This estimate was largely derived from populations of European ancestry among high income nations. There is a lack of data on FH from large regions in the world and few studies exist on individuals of African ancestry. To address this gap, we examined the prevalence and phenotype of FH among over 70,000 individuals of African ancestry. We hypothesized that the prevalence and phenotype of FH is the same between African and European ancestry groups.
Methods: All of Us and Geisinger’s MyCode are US-based healthcare cohorts with linked genomic sequence data and electronic health record data on over 450,000 participants. Genetic variants were collected from canonical FH genes: LDLR, APOB, and PCSK9. Variants meeting criteria provided by the ClinGen Variant Curation Expert Panel FH guidelines were classified as pathogenic/likely pathogenic (P/LP) or variants of unknown significance (VUS). Participants were assigned into one of four ancestry groups (AFR, ASN, EUR and unclassified) using Rye.
Results: We identified 211 individuals in the AFR group with a P/LP variant and 203 with a VUS. Among EUR individuals, 1,435 had a P/LP variant and 762 had a VUS. The prevalence of a P/LP variant was significantly lower in the AFR group (1 in 342) compared to the EUR group (1 in 273) (p=0.003); however, the prevalence of VUS variants was significantly higher with 1 in 356 in the AFR group compared to 1 in 515 in the EUR group (p=2.8 x10^-6). The AFR group was more likely to have a P/LP variant in LDLR compared to the EUR group. In All of Us, AFR individuals with a P/LP variant had pretreatment LDL-C levels of 223.0 mg/dL, versus 122.8 mg/dL without a variant. In MyCode, levels were 242.7 mg/dL with a variant and 125.6 mg/dL without. Notably, pretreatment LDL-C was significantly higher in AFR individuals with a P/LP variant (35.8 mg/dL, p=0.001) compared to EUR individuals.
Conclusions: The prevalence of P/LP FH variants is lower in AFR than in EUR individuals, but the LDL-C phenotype is more severe, likely due to a higher prevalence of LDLR variants. VUS variants are more common in AFR, possibly reflecting a lack of clinical data in genetic databases. These findings highlight the need for more diversity in FH studies.