Characterizing genetic profiles for high triglyceride levels in U.S. patients of African ancestry

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ABSTRACT Hypertriglyceridemia (HTG) is a common cardiovascular risk factor characterized by elevated circulating triglyceride (TG) levels. Researchers have assessed the genetic factors that influence HTG in studies focused predominantly on individuals of European ancestry (EA). However, relatively little is known about the contribution of genetic variation to HTG in people of AA, potentially constraining research and treatment opportunities; the lipid profile for African ancestry (AA) populations differs from that of EA populations—which may be partially attributable to genetics. Our objective was to characterize genetic profiles among individuals of AA with mild-to-moderate HTG and severe HTG versus those with normal TGs by leveraging whole genome sequencing (WGS) data and longitudinal electronic health records (EHRs) available in the All of Us (AoU) program. We compared the enrichment of functional variants within five canonical TG metabolism genes, an AA-specific polygenic risk score for TGs, and frequencies of 145 known potentially causal TG variants between patients with HTG and normal TG among a cohort of AA patients (N=15,373). Those with mild-to-moderate HTG (N=342) and severe HTG (N≤20) were more likely to carry APOA5 p.S19W (OR=1.94, 95% CI [1.48-2.54], p=1.63×10 -6 and OR=3.65, 95% CI [1.22-10.93], p=0.02, respectively) than those with normal TG. They were also more likely to have an elevated (top 10%) PRS, elevated carriage of potentially causal variant alleles, and carry any genetic risk factor. Alternative definitions of HTG yielded comparable results. In conclusion, individuals of AA with HTG were enriched for genetic risk factors compared to individuals with normal TGs.

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