Key result
Triglyceride-associated genetic variants were significantly associated with lipid and cardiovascular phenotypes in European ancestry cohorts (9 of 10 variants), but showed limited effects in African ancestry cohorts (1 of 6 variants), with few secondary pleiotropic effects detected in either group.
Why the study?
Drugs targeting triglyceride-associated genes may improve cardiovascular outcomes, but potential additional benefits or deleterious effects of such targeting remain poorly understood.
Do genetic variants associated with triglyceride lowering reduce cardiovascular phenotypes and have pleiotropic effects in European and African ancestry populations?
Observational (n=204,864)
Yes
Do genetic variants associated with triglyceride lowering reduce cardiovascular phenotypes and have pleiotropic effects in European and African ancestry populations?
Genetic proxies for triglyceride-lowering medications show expected lipid and cardiovascular benefits with few deleterious pleiotropic effects in European ancestry populations, but these targets may be less effective in African ancestry populations.
Ancestry-specific TG variant effects caution against generalizing European genetic findings to African ancestry; leaves open validation in diverse cohorts for CV risk prediction.
Drugs targeting triglyceride (TG)-associated genes have the potential to improve cardiovascular outcomes. However, we know little regarding the potential additional benefits or deleterious effects of such targeting. As such, in ancestry-specific cohorts of European ancestry (EA) and African ancestry (AA) at Vanderbilt (BioVU), we used PheWAS to test associations between measured TG levels and validated variants previously associated with TG levels in Mendelian randomization studies. We replicated results in All of Us (AoU). In the BioVU EA cohort (n=63,094), 9 of 10 validated SNPs had significant or suggestive associations with lipid and cardiovascular phenotypes, largely consistent with AoU participants of EA (n=97,545). In the BioVU AA cohort (n=12,515) and AoU AA cohort (n=31,710), results were more limited; only 1 of 6 validated SNPs was significantly associated with a lipid or cardiovascular phenotype in either BioVU or AoU, and no significant or suggestive associations were consistent across both cohorts. We detected few secondary effects in either EA or AA BioVU patients, and none were replicated. These results suggest that there may be limited additional benefits, but few deleterious effects, associated with targeting known TG-associated genes. However, these targets may not be as effective for mitigating cardiovascular risk among individuals of AA.
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Outland et al. (2025) conducted an observational in Elevated triglycerides and cardiovascular risk (n=204,864). Triglyceride-associated genetic variants (e.g., APOA5, LPL, APOC3, ANGPTL3, ANGPTL4) vs. Reference alleles (non-carriers) was evaluated on Associations with prespecified lipid, cardiovascular, and other clinical phenotypes via PheWAS. Triglyceride-associated genetic variants were significantly associated with lipid and cardiovascular phenotypes in European ancestry cohorts (9 of 10 variants), but showed limited effects in African ancestry cohorts (1 of 6 variants), with few secondary pleiotropic effects detected in either group.
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