Genetic modulation of omega-3 and omega-6 polyunsaturated fatty acid metabolism and health outcomes: a systematic review

Abstract

Inter-individual responses to omega-3 and omega-6 polyunsaturated fatty acid (PUFA) interventions vary substantially, complicating standardized dietary recommendations and suggesting a role for genetic differences that influence fatty acid biosynthesis, metabolism, and downstream health effects. A PRISMA 2020-guided systematic search of PubMed, Embase, and Web of Science identified adult studies assessing nutrigenetic interactions in the context of PUFA interventions and outcomes, yielding 132 eligible studies (79 Tier 1; 53 Tier 2) that collectively indicate pathway-specific genetic control of PUFA handling. Across 38 studies (combined n ≈ 500 000), variants in FADS1/FADS2 were consistently associated with genotype-dependent differences in long-chain PUFA synthesis, with minor allele carriers showing ∼40–60% lower conversion efficiency (14 studies reported significant interactions). In 25 studies (n ≈ 930 000), APOE ε4 carriage was associated with attenuated DHA responses to supplementation (≈20–31% lower) and markedly faster DHA turnover (≈77% shorter half-life), with significant interactions reported in 13 studies. Additional loci showed context-dependent effects, including lower type 2 diabetes odds among TCF7L2 TT carriers with high omega-3 intake (∼42% reduction) and substantially greater EPA uptake among FABP2 Thr54 carriers (up to ∼12-fold). Overall, genetic variation appears to shape omega-3 and omega-6 PUFA bioavailability and metabolism through mechanistically coherent pathways, providing a plausible explanation for inconsistent population-level intervention effects and supporting a shift toward genetically informed precision nutrition strategies for both PUFA families.