rs174537 — FADS1

FADS1 rs174537 — Your Fatty Acid Conversion Throttle

Deep within the FADS gene cluster on chromosome 11, rs174537 sits in a regulatory region that acts as a master volume control for FADS1¹¹ FADS1
Fatty acid desaturase 1, also called delta-5 desaturase (D5D), the enzyme that converts DGLA to arachidonic acid in the omega-6 pathway and ETA to EPA in the omega-3 pathway. This single nucleotide change — G versus T — determines how much FADS1 enzyme your cells produce, and in turn how efficiently your body converts plant-based omega-3 and omega-6 fats into their biologically active long-chain forms. Because the Western diet overwhelmingly supplies omega-3 fats as the short-chain precursor alpha-linolenic acid (ALA) from flaxseed, chia, and walnuts, your FADS1 genotype directly determines whether that plant-based omega-3 reaches your cells as EPA and ultimately DHA.

The Mechanism

rs174537 does not change the FADS1 protein itself — it acts upstream. The T allele increases DNA methylation of the FADS1 promoter region²² increases DNA methylation of the FADS1 promoter region
Allele-specific methylation studies in CD4+ cells and leukocytes confirm rs174537 T allele associates with higher methylation at a CpG site in the FADS1 promoter (Chr11:61584894), silencing transcription, which reduces how much FADS1 messenger RNA is transcribed and ultimately how much FADS1 enzyme is produced. Eight CpG sites within a putative enhancer region between FADS1 and FADS2 also show significant allele-specific methylation linked to this SNP. Lower FADS1 expression means slower conversion of: - Dihomo-gamma-linolenic acid (DGLA) → arachidonic acid (AA) in the omega-6 pathway - Eicosatetraenoic acid (ETA) → eicosapentaenoic acid (EPA) in the omega-3 pathway G allele carriers produce more FADS1 enzyme, converting more precursor fatty acids into their long-chain products. The practical result: GG homozygotes have higher circulating AA and higher baseline EPA (from endogenous conversion of plant ALA); TT homozygotes have lower AA and substantially lower EPA.

The Evidence

The landmark finding came from a genome-wide association study of plasma PUFAs in 1,075 participants³³ genome-wide association study of plasma PUFAs in 1,075 participants
Tanaka et al. 2009, InCHIANTI Study, PLoS Genetics where rs174537 showed the strongest GWAS signal for arachidonic acid (p = 5.95×10⁻⁴⁶) and explained a remarkable 18.6% of all additive variance in AA levels — an unusually large effect for a common SNP. The same variant significantly associated with EPA levels (p = 1.07×10⁻¹⁴) and eicosadienoic acid (p = 6.78×10⁻⁹). Population data confirmed the clinical stakes: in a comparative study of European Americans and African Americans, TT homozygotes had AA levels 26% lower than GG carriers⁴⁴ TT homozygotes had AA levels 26% lower than GG carriers
Sergeant et al. 2012, British Journal of Nutrition: TT 6.3±1.0% vs GG 8.5±2.1% of total fatty acids; p=3.0×10⁻⁵. The AA/DGLA ratio (a direct measure of FADS1 enzyme activity) was nearly half in TT versus GG carriers (3.4 vs 6.5, p=2.2×10⁻⁷). The cardiovascular implications cut both ways. Higher FADS1 activity (GG) produces more AA — the omega-6 precursor to pro-inflammatory eicosanoids — and is linked to higher LDL cholesterol and elevated CAD risk in T2D patients⁵⁵ higher LDL cholesterol and elevated CAD risk in T2D patients
T2D with GG genotype: OR=1.76 (95%CI 1.14–2.72) for combined T2D+CAD; elevated plasma LDL and delta-6 desaturase activity. Meanwhile, lower FADS1 activity (TT) reduces AA production but also impairs the endogenous pathway to EPA, leaving TT carriers dependent on preformed EPA from marine sources. A 12-week fish oil intervention study⁶⁶ 12-week fish oil intervention study
Roke and Mutch, Nutrients 2014 found that T allele carriers had 48% lower baseline serum EPA compared to GG homozygotes (p=0.04), yet when given 1.8 g EPA+DHA daily, T allele carriers showed a significantly greater percentage increase in red blood cell EPA incorporation (p=9.1×10⁻³). This confirms that while T carriers start with lower EPA, they absorb and incorporate supplemental EPA effectively.

Practical Actions

For T allele carriers (GT and TT): because endogenous EPA synthesis from ALA is reduced, relying on plant-based omega-3 sources (flaxseed, chia, walnuts) is insufficient to maintain adequate EPA levels. Direct supplementation with preformed EPA and DHA from marine sources or algae-based supplements bypasses the impaired conversion step entirely. Target 2–4 g combined EPA+DHA daily for TT homozygotes; 1–2 g for GT heterozygotes. For GG homozygotes: higher FADS1 activity means dietary omega-6 converts more efficiently to AA. When background omega-6 intake is high (typical Western diet with sunflower, corn, or soybean oil), this efficiently produces excess AA and pro-inflammatory eicosanoids. Shifting the omega-6:omega-3 ratio — increasing marine omega-3 and reducing omega-6 cooking oils — is the most evidence-based dietary adjustment.

Interactions

rs174537 is in high linkage disequilibrium (r² > 0.8) with rs174547 and rs174546 in the same FADS1 haplotype block. These variants co-segregate and may produce additive effects on FADS1 expression. Carrying multiple minor alleles across the FADS1 cluster compounds the reduction in desaturase activity. The FADS1 locus also interacts with dietary omega-6 intake: high linoleic acid (LA) intake combined with efficient FADS1 (GG) preferentially drives AA production. Conversely, in TT carriers on a low marine omega-3 diet, the impaired conversion capacity creates a functional EPA/DHA deficiency even with adequate ALA intake. This gene-diet interaction means the same dietary pattern produces very different PUFA profiles depending on FADS1 genotype — a key argument for personalized omega-3 supplementation guidance.