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 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. | 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 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 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 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.
Alla genotyper
Normal FADS2 activity — efficient conversion of dietary fats
You carry two copies of the common C allele at rs174575, associated with normal delta-6 desaturase activity. Your body converts plant-based omega-3 (ALA) and omega-6 (LA) precursors into their long-chain active forms — EPA, DHA, and arachidonic acid — with typical efficiency. About 56% of people globally share this genotype, though frequencies vary: more than 90% of South Asians carry CC, while it is less common (~47% globally among East Asians). This means plant sources of omega-3 (flax, chia, walnuts) contribute meaningfully to your EPA/DHA levels, though marine sources remain the most efficient delivery mechanism.
Moderately reduced FADS2 activity — partially impaired omega-3 conversion
You carry one G allele at rs174575, which modestly reduces FADS2 delta-6 desaturase activity. You convert plant-based omega-3 (ALA) and omega-6 (LA) precursors to long-chain forms with somewhat less efficiency than CC individuals. Your circulating EPA and DHA levels from plant sources will be lower than average for the same dietary intake. About 38% of people globally share this heterozygous genotype. Relying entirely on plant-based omega-3 may leave your EPA and DHA levels suboptimal. Including marine sources or supplements ensures adequate delivery of the preformed long-chain omega-3s your body needs.
Substantially reduced FADS2 activity — plant omega-3 is an unreliable EPA/DHA source
You carry two copies of the G allele at rs174575, which substantially reduces FADS2 delta-6 desaturase activity. Your body has significantly impaired ability to convert plant-based omega-3 (ALA from flax, chia, walnuts) into EPA and DHA, and reduced capacity to convert linoleic acid to arachidonic acid. Precursor fatty acids accumulate while downstream long-chain PUFAs remain low. About 6% of people globally are GG homozygous, though frequencies are somewhat higher in Latino populations (~10%) and lower in South Asians (~2%). Plant omega-3 sources are not an effective strategy for raising EPA and DHA in your body — you need preformed long-chain omega-3s directly from marine or algae-based sources.