(OR20-02-26) Pinpointing Genetic Factors Underlying Race-Associated Heterogeneity in Omega-3 Fatty Acid Response

Objectives: Randomized trials suggest greater cardiovascular benefit from long-chain omega-3 fatty acid (LCN3FA) supplementation in self-reported Black versus White individuals, yet the biological basis remains unresolved. Genetics is a likely contributing factor given the known ancestry-correlated variation in FADS genes, which affect fatty acid metabolism. We aimed to first confirm this population heterogeneity with respect to cardiovascular risk factors (CRFs) in a large observational data setting, then explore whether FADS genetic variation explains this heterogeneity.

Methods: We primarily analyzed data from the UK Biobank (UKB; N ~ 200,000). Dietary LCN3FA from fish and fish oil supplements was estimated from questionnaires and plasma LCN3FA status was assessed via NMR. Outcomes included lipid (LDL- and HDL-cholesterol, triglycerides), inflammatory (hsCRP), and glycemic (hemoglobin A1c) CRFs. We tested for interactions between genetically-inferred ancestry and LCN3FA intake on both plasma LCN3FA status and CRFs. Replication of ancestry and FADS effect modification was sought in the TOPMed cohorts (FHS, WHI, and MESA; N ~ 5,000 with plasma LCN3FA from LC-MS).

Results: Consistent with trial evidence, UKB results showed significant ancestry heterogeneity in LCN3FA-CRF relationships for 3/5 CRFs: LDL, HDL, and hsCRP. This was strongest for LDL (p-interaction = 7x10^-5), with a more pronounced LDL-increasing effect of LCN3FA in European compared to African ancestry. FADS tag variant rs174576 significantly modified LCN3FA associations with plasma status (previously reported) and LDL (p = 0.001). TOPMed results supported ancestry heterogeneity in the LCN3FA intake-status and intake-LDL relationships (p = 0.01 and p = 0.002). FADS variation replicated for the status relationship (p = 0.007) but not LDL (p = 0.2). In UKB, genetic ancestry remained an independent modifier of LCN3FA-LDL effects after accounting for FADS, suggesting additional genetic contributors.

Conclusions: Our results support reported race-associated heterogeneity in LCN3FA response and suggest a previously underappreciated role of LDL-cholesterol, supporting a move from race-based to genetically-informed dietary recommendations.

Funding Sources: NIH - NIDDK