rs174575 — FADS2

FADS2 rs174575 — The Bottleneck Before EPA and DHA

Buried in an intron of the FADS2 gene on chromosome 11, rs174575 is one of the most studied variants in human fatty acid metabolism. FADS2 encodes delta-6 desaturase¹¹ delta-6 desaturase
The enzyme that performs the first desaturation step in both the omega-6 and omega-3 elongation pathways, acting before FADS1 (delta-5 desaturase) in the cascade, the rate-limiting enzyme that initiates the conversion of short-chain dietary fats into their biologically active long-chain forms. Without adequate delta-6 desaturase activity, the pathway stalls before it can produce gamma-linolenic acid (GLA) from linoleic acid, or stearidonic acid (SDA) from alpha-linolenic acid — the precursors to all downstream omega-6 and omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) including arachidonic acid, EPA, and DHA.

The Mechanism

The rs174575 G allele acts through an intronic regulatory mechanism that reduces FADS2 enzyme expression and activity. The result is a classic substrate-product inversion: G allele carriers accumulate the upstream precursors linoleic acid (LA) and alpha-linolenic acid (ALA) while producing less of the downstream products arachidonic acid (ARA), EPA, and DHA. Because FADS2 acts at the very first desaturation step, its impairment affects both the omega-6 and omega-3 pathways simultaneously — reducing the body's ability to make any of the long-chain PUFAs from plant-based sources.

The effect is additive: each G allele further reduces desaturase activity, with GG homozygotes showing the most pronounced accumulation of precursors and reduction in end-products.

The Evidence

The strongest epidemiological evidence comes from a large longitudinal study by Steer et al.²² large longitudinal study by Steer et al.
Steer CD et al. Polyunsaturated fatty acid levels in blood during pregnancy, at birth and at 7 years: their associations with two common FADS2 polymorphisms. PLoS ONE, 2012 that followed 4,342 pregnant women through to their children at 7 years. The G allele showed strong positive associations with the substrates linoleic acid and alpha-linolenic acid, and corresponding negative associations with downstream highly unsaturated fatty acids including arachidonic acid, EPA, and DHA — at all three developmental time points studied (pregnancy, birth, and age 7).

A meta-analysis of 10 studies³³ meta-analysis of 10 studies
Liu et al. Meta-analysis of FADS2 rs174575 and long-chain PUFA levels. Br J Nutr, 2024 confirmed that G allele carriers have significantly elevated dihomo-γ-linolenic acid (P=0.005) and linoleic acid (P=0.002) alongside reduced arachidonic acid (P=0.033). In breast milk specifically, G allele carriers showed elevated dihomo-γ-linolenic acid (P=0.050) and reduced arachidonic acid (P=0.030) — directly relevant for infant nutrition.

A study of 250 pregnant women found that G allele carriers had significantly lower plasma EPA⁴⁴ G allele carriers had significantly lower plasma EPA
Carvalho GQ et al. Maternal polymorphisms in the FADS1 and FADS2 genes modify the association between PUFA ingestion and plasma concentrations of omega-3 polyunsaturated fatty acids. Clin Nutr, 2019 at moderate dietary LA/ALA ratios, with the genotype modifying how dietary omega-3 intake translates into circulating EPA levels.

Beyond fatty acid levels, FADS2 activity has downstream metabolic consequences. In Chinese Han individuals, G allele minor-allele carriers had lower erythrocyte arachidonic acid⁵⁵ G allele minor-allele carriers had lower erythrocyte arachidonic acid
Huang T et al. Genetic variants in desaturase gene, erythrocyte fatty acids, and risk for type 2 diabetes in Chinese Hans. Prostaglandins Leukot Essent Fatty Acids, 2014, and higher circulating omega-3 PUFAs were associated with lower type 2 diabetes risk.

Practical Implications

The critical implication of rs174575 G allele carriage is that plant-based omega-3 sources (flaxseed, chia seeds, walnuts, hemp) are much less useful than they would be for CC individuals. These foods supply ALA — but FADS2 must act first to begin converting ALA toward EPA and DHA. With impaired FADS2 activity, ALA accumulates rather than converting. Even at high dietary intakes, G allele carriers generate less EPA and DHA from plant sources than CC individuals at lower intakes.

This is particularly relevant for individuals on plant-based diets, where marine sources are excluded and the entire omega-3 strategy depends on conversion from ALA. For GG homozygotes on such diets, functional omega-3 deficiency is likely without targeted supplementation.

Breast milk composition is also affected — lactating G allele carriers produce milk with lower arachidonic acid and DHA, potentially impacting infant neurodevelopmental outcomes.

Interactions

rs174575 functions upstream in the FADS pathway from rs174547 (FADS1), which controls the subsequent delta-5 desaturation step. Individuals carrying G alleles at rs174575 and C alleles at rs174547 face a double bottleneck in the PUFA cascade — impaired delta-6 activity reduces the substrate available for delta-5 to convert, and then impaired delta-5 further reduces end-product yield. The practical effect is additive impairment of the entire endogenous pathway from LA/ALA to ARA/EPA/DHA.

rs1535 is another FADS2 intronic variant often studied alongside rs174575; the two are in moderate linkage disequilibrium in European populations, and rs1535 shows similar biological effects on PUFA levels.