FADS2

FADS2 rs1535 — A Stronger Delta-6 Signal and a Cardiac Responder Marker

The FADS2 gene on chromosome 11 encodes delta-6 desaturase | The rate-limiting
enzyme that performs the first desaturation step in long-chain PUFA synthesis,
converting linoleic acid (LA) to GLA and alpha-linolenic acid (ALA) to stearidonic
acid — the upstream gating step before all further elongation and desaturation to
EPA, DHA, and arachidonic acid, the rate-limiting enzyme that opens the
door to all long-chain polyunsaturated fatty acid synthesis from dietary plant
precursors. rs1535 is an intronic FADS2 variant studied in large multi-generational
cohorts, and it carries a specific distinction among the FADS2 variants on this
platform: it shows consistently stronger associations with PUFA substrate accumulation
than the nearby rs174575, and it has been prospectively validated as a pharmacogenomic
marker identifying who benefits most from omega-3 supplementation after a heart attack.

The Mechanism

Like rs174575, rs1535 acts through an intronic regulatory mechanism that reduces FADS2
expression and delta-6 desaturase activity. The G allele causes the same fundamental
substrate-product inversion seen across the FADS2 locus: precursors linoleic acid (LA)
and alpha-linolenic acid (ALA) accumulate while downstream products — gamma-linolenic
acid (GLA), arachidonic acid (ARA), EPA, and DHA — are reduced. The effect is additive:
each G allele further suppresses delta-6 desaturase function, with GG homozygotes
showing the most pronounced phenotype.

The two FADS2 variants rs1535 and rs174575 are in high but incomplete linkage
disequilibrium (r² = 0.66, D' = 0.97 in European populations | Steer et al.
Human Molecular Genetics, 2012),
meaning they travel together most but not all of the time and can be detected
as partially independent signals in large cohorts.

The Evidence

The largest longitudinal evidence comes from the Avon Longitudinal Study of Parents
and Children, reported 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. Human Molecular Genetics, 2012
in 4,342 pregnant mothers, 3,343 cord blood samples, and 5,240 children at age 7.
Crucially, the authors analyzed both rs1535 and rs174575 in the same sample and
found rs1535 had consistently stronger PUFA associations — with approximately 60%
larger effect sizes for omega-6 substrates such as linoleic acid. At age 7, the
rs1535 G allele showed a negative association with arachidonic acid of β=−0.640
(SE 0.019, p<10⁻⁹) and accounted for approximately 18% of the variance in
circulating ARA — a larger explained variance than rs174575 at the same locus.

The clinical implications extend beyond fatty acid levels. The OMEGA-REMODEL
randomized trial of high-dose omega-3 fatty acids in 358 post-myocardial infarction
patients used rs1535 genotyping as a pharmacogenomic marker. In a post-hoc analysis
by Kwong et al. | Kwong RY et al. Genetic profiling of fatty acid desaturase
polymorphisms identifies patients who may benefit from high-dose omega-3 fatty
acids in cardiac remodeling after acute myocardial infarction. PLoS One, 2019
of 312 genotyped patients, GG homozygotes showed dramatically greater benefit from
omega-3 supplementation: left ventricular end-systolic volume index improved by
−4.4 ml/m² on omega-3 versus +1.2 ml/m² on placebo (p=0.006), an odds ratio of
7.2 for clinically meaningful improvement — compared to an OR of 1.2 in AA carriers.
NT-proBNP and galectin-3 (cardiac remodeling biomarkers) were similarly reduced
only in GG patients on omega-3.

For lactating mothers, rs1535 has been associated with breast milk PUFA composition
in studies of Chinese and Taiwanese women. Ding et al. | Ding Z et al. Association
of polyunsaturated fatty acids in breast milk with fatty acid desaturase gene
polymorphisms among Chinese lactating mothers. Prostaglandins Leukot Essent Fatty
Acids, 2016 found that minor allele
carriers at rs1535 had lower concentrations of GLA and arachidonic acid in breast
milk in 209 Chinese women, while Wu et al. | Wu BH et al. FADS Genetic Variants
in Taiwanese Modify Association of DHA Intake and Its Proportions in Human Milk.
Nutrients, 2020 demonstrated that
accumulated G allele dose at rs1535 was associated with lower breast milk DHA
proportions in 164 Taiwanese mothers, with a gene-diet interaction: low-DHA-intake
mothers carrying the G allele showed the lowest milk DHA concentrations.

Practical Actions

The core implication of G allele carriage at rs1535 is identical to the broader
FADS2 picture: plant-based omega-3 sources (flax, chia, walnuts) supply ALA that
cannot efficiently convert to EPA and DHA when delta-6 desaturase is impaired.
Preformed EPA and DHA from marine or algae-based sources bypass the blocked first
step. The unique addition from rs1535 research is the cardiac intervention signal:
GG homozygotes recovering from a myocardial infarction had a 7-fold greater
probability of cardiac improvement on high-dose omega-3, which is a level of
pharmacogenomic specificity not demonstrated for rs174575 alone.

For lactating mothers with GG genotype, the breast milk DHA deficit creates an
additional reason to prioritize preformed DHA supplementation during pregnancy
and lactation — not just for their own circulating EPA/DHA status but for the
DHA content of milk their infants receive.

Interactions

rs1535 and rs174575 are both intronic FADS2 variants in high LD (r²=0.66) with
overlapping but not identical biological signals. Individuals carrying G alleles
at both rs1535 and rs174575 have additive impairment of delta-6 desaturase activity.
Both variants also interact functionally with the downstream FADS1 delta-5
desaturase variants (rs174547, rs174537): reduced delta-6 output from FADS2 limits
the substrate available for FADS1 to act on, compounding the PUFA synthesis deficit
when both genes carry risk alleles.