rs174572 — FADS2

FADS2 rs174572 — The Delta-6 Desaturase Gatekeeper

Before your body can build the long-chain omega-3s and omega-6s it needs for every cell membrane, every eicosanoid signal, and every synapse, it must pass dietary fatty acids through a molecular gateway: delta-6 desaturase¹¹ delta-6 desaturase
FADS2 (fatty acid desaturase 2) encodes delta-6 desaturase, the enzyme that inserts a double bond at the Δ6 position in both the omega-3 and omega-6 pathways. rs174572, an intronic variant in FADS2, alters how efficiently this gateway works. The T allele is associated with reduced desaturase activity and measurably lower circulating EPA — the omega-3 that drives anti-inflammatory eicosanoid production, platelet function, and cardiovascular protection.

The Mechanism

Delta-6 desaturase catalyzes the first and rate-limiting step in two parallel pathways: - Omega-6: linoleic acid (LA, 18:2n-6) → gamma-linolenic acid (GLA, 18:3n-6) - Omega-3: alpha-linolenic acid (ALA, 18:3n-3) → stearidonic acid (SDA, 18:4n-3)

Without adequate D6D activity, dietary precursors accumulate (higher LA and ALA in plasma) while downstream products (GLA, stearidonic acid, and ultimately EPA, DHA, and AA) remain low. rs174572 sits in intron 1 of FADS2, and — consistent with findings in the broader FADS locus — likely affects FADS2 promoter methylation and transcriptional activity²² FADS2 promoter methylation and transcriptional activity
Allele-specific methylation at FADS cluster intronic and promoter CpG sites has been confirmed in multiple tissues; intronic SNPs in high LD with the cluster tag this regulatory effect. T allele carriers produce less FADS2 enzyme, throttling both pathways simultaneously.

The Evidence

The most direct evidence comes from a genome-wide fatty acid study of 1,144 European adolescents in the HELENA cohort³³ genome-wide fatty acid study of 1,144 European adolescents in the HELENA cohort
Bokor et al. J Lipid Res 2010; 51:2325–2333; 13 FADS SNPs genotyped across 9 European countries. Carriers of the minor T allele at rs174572 showed significantly higher plasma LA (p=0.0009), higher ALA (p=0.0002), and higher DGLA — precursors that had not been converted downstream. Simultaneously, arachidonic acid was lower (p<1×10⁻⁶) and EPA was substantially lower (p=4.2×10⁻⁶). The D5D activity index (which reflects the overall efficiency of the cascade) fell from 3.70 in CC homozygotes to 3.06 in CT heterozygotes and 2.60 in TT homozygotes (p=6.1×10⁻³¹) — one of the strongest genotype-to-enzyme associations observed in the FADS gene cluster.

A 2024 scoping review of 40 studies⁴⁴ 2024 scoping review of 40 studies
Loukil, Mutch & Plourde, Genes Nutr 2024; DOI: 10.1186/s12263-024-00747-4 confirmed that minor allele carriers of rs174572 have lower circulating EPA, placing this SNP among the FADS variants with documented EPA-specific associations.

The cardiovascular relevance of FADS-driven PUFA imbalances is documented in a study of 876 subjects⁵⁵ study of 876 subjects
Martinelli et al. Am J Clin Nutr 2008 where a high AA-to-LA ratio (reflecting high D5D activity, the opposite of what T allele carriers have) independently predicted CRP elevation and coronary artery disease risk (OR ~2.55). For T allele carriers, the clinical concern is the mirror image: chronically low EPA results in reduced production of anti-inflammatory eicosanoids (prostaglandin E3, thromboxane A3) and inadequate cardiovascular protection from omega-3 signaling — without the genetic test, this functional deficiency is invisible.

Practical Actions

Because D6D activity is the first committed step in PUFA synthesis, T allele carriers cannot compensate by eating more flaxseed, chia, or walnuts. Those sources supply ALA, which still must pass through the impaired D6D gate before becoming stearidonic acid, EPA, or DHA. The only reliable route to adequate EPA is preformed EPA from marine or algae sources that bypass the conversion step entirely.

For TT homozygotes — the most affected genotype — supplementation with 2–4 g combined EPA+DHA daily from concentrated fish oil or algae-based sources is the most targeted approach. For CT heterozygotes, 1–2 g daily represents a reasonable starting point. The omega-3 index (erythrocyte EPA+DHA percentage) provides a direct, individualized measure of whether supplementation is achieving adequate tissue levels.

Interactions

rs174572 is located near rs174547, rs174546, rs174537, rs174575, and rs174589 in the FADS gene cluster on chromosome 11q12.2. These variants co-segregate as haplotype blocks, and carrying T alleles across multiple FADS cluster SNPs compounds the reduction in overall PUFA conversion capacity. The functional impact is therefore greater in individuals who carry risk alleles at both FADS2 (rs174572, D6D — the first step) and FADS1 (rs174537 or rs174547, D5D — the downstream step), as both desaturase steps become rate-limited simultaneously. This combination represents a proposal for a compound action (see harvesting notes).