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.
Genetic modulation of omega-3 and omega-6 polyunsaturated fatty acid metabolism and health outcomes: A systematic review
Visioli, FrancescoConceptualization
;
2026
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.
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