rs174537 — FADS1

Regulatory variant in the FADS1 locus that controls delta-5 desaturase expression, altering conversion of omega-6 and omega-3 precursors to long-chain PUFAs; the G allele drives higher arachidonic acid and cardiovascular risk while the T allele impairs EPA synthesis from plant-based omega-3

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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 reduces how much FADS1 messenger RNA is transcribed and ultimately how much FADS1 enzyme is produced. 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 participants22 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 = 1.04×10⁻¹⁴) 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 carriers33 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 patients44 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 study55 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. 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.

Nutrient Interactions

omega-3 fatty acids (ALA) impaired_conversion
eicosapentaenoic acid (EPA) increased_need
arachidonic acid (AA) altered_metabolism
omega-6 fatty acids (LA/DGLA) altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GT Intermediate Desaturase Activity Intermediate

One G allele — moderately elevated arachidonic acid with partial EPA synthesis

You carry one copy of the G allele and one copy of the T allele at rs174537. This heterozygous genotype gives you intermediate FADS1 (delta-5 desaturase) activity — more efficient than TT homozygotes, but with somewhat less AA production than GG carriers. About 43% of people of European descent share this genotype. GT carriers sit in the middle: baseline EPA levels will be lower than in GG homozygotes, meaning plant-based ALA converts to EPA less efficiently than for GG carriers. At the same time, AA production from omega-6 precursors is somewhat attenuated compared to GG. A moderate dose of preformed EPA/DHA is the most targeted approach.

GG High Desaturase Activity High Risk

Highly efficient FADS1 — elevated arachidonic acid and cardiovascular risk

Efficient delta-5 desaturase production accelerates the final step of AA synthesis: DGLA → AA. This creates a physiological state where any dietary linoleic acid (omega-6, abundant in seed oils) efficiently flows through the desaturation cascade to AA. The same mechanism also applies in the omega-3 pathway: GG carriers convert plant-derived ALA more efficiently to EPA, meaning their baseline EPA levels are higher than T allele carriers even without supplementation. In clinical fish oil intervention studies, GG homozygotes showed consistently higher baseline serum EPA and higher ARA/DGLA ratios across all timepoints — a direct readout of their elevated D5D activity. The cardiovascular relevance is well-documented: AA is the substrate for thromboxane A2 (platelet aggregation), prostaglandin E2 (inflammation), and leukotriene B4 (immune activation). A Western diet high in omega-6 cooking oils supplies the raw material; high FADS1 activity ensures it reaches AA. The dietary intervention that most directly addresses this — replacing omega-6-rich cooking oils with olive oil and increasing marine omega-3 intake — shifts the competitive balance away from AA toward EPA-derived eicosanoids.

TT Reduced Desaturase Activity Poor Converter

Two T alleles — substantially reduced FADS1 activity and impaired EPA synthesis from plant sources

Functional studies in 3D human hepatic constructs confirmed that rs174537 T allele cells show markedly reduced FADS1 activity. This affects both major PUFA pathways simultaneously: the omega-6 pathway produces less AA from DGLA, and the omega-3 pathway produces less EPA from the intermediate eicosatetraenoic acid (ETA). The positive consequence: lower AA means a lower baseline for AA-derived pro-inflammatory eicosanoids (thromboxane A2, prostaglandin E2, leukotriene B4), and TT carriers tend to show lower LDL cholesterol compared to GG in cardiovascular cohort studies. The critical consequence for nutrition: a person cannot compensate for impaired FADS1 activity by eating more flaxseeds. The conversion ceiling is set genetically. The fish oil supplementation intervention study (Roke and Mutch, 2014) confirmed that while T allele carriers start with 48% lower EPA, they absorb and incorporate supplemental preformed EPA very efficiently — showing greater percentage gains in red blood cell EPA than GG homozygotes. This makes targeted supplementation highly effective once the need is recognized.