rs1535 — FADS2

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

The FADS2 gene on chromosome 11 encodes delta-6 desaturase¹¹ 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 populations²² 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.³³ 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.⁴⁴ 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.⁵⁵ 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.⁶⁶ 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.