rs174535 — MYRF

MYRF rs174535 — A Gateway Variant for Omega-3 Status in the FADS Region

Chromosome 11's 11q12 region is home to one of the most influential loci for polyunsaturated fatty acid (PUFA) metabolism in the human genome — the FADS gene cluster encoding the delta-5 and delta-6 desaturase enzymes that convert dietary fatty acid precursors into the long-chain omega-3 and omega-6 fatty acids your cells actually use. rs174535 sits within the MYRF gene¹¹ MYRF gene
Myelin Regulatory Factor, a transcription factor encoded at chr11:61,752,636–61,788,518 whose primary known function is promoting oligodendrocyte differentiation and central nervous system myelination, approximately 55 kilobases downstream of the FADS1 gene. Despite MYRF's primary role in myelin biology, carriers of the rs174535 C allele consistently show lower circulating omega-3 PUFA and DHA concentrations — a finding that has reached genome-wide significance in independent cohorts.

The Mechanism

rs174535 creates a missense substitution (Ser1051Arg) in MYRF isoform 2. Whether this amino acid change directly alters fatty acid metabolism is uncertain — MYRF is not known to participate in lipid desaturation pathways. The more plausible explanation is linkage disequilibrium (LD)²² linkage disequilibrium (LD)
A statistical correlation between nearby genetic variants meaning they are co-inherited more often than expected by chance; variants in the same haplotype block act as proxies for each other in association studies with functional variants in the FADS1 and FADS2 genes immediately upstream. The entire 11q12.2 region — spanning FADS1, FADS2, FADS3, TMEM258, FEN1, and MYRF — shows strong patterns of LD, meaning rs174535 may function as a tag SNP capturing the effect of nearby FADS variants on the same haplotype. A secondary possibility, not yet ruled out, is that Ser1051Arg alters MYRF's transcriptional targets in a way that indirectly feeds back on lipid homeostasis.

The Evidence

The primary evidence comes from a genome-wide association study of serum omega-3 and omega-6 PUFA concentrations³³ genome-wide association study of serum omega-3 and omega-6 PUFA concentrations
Coltell et al., Nutrients 2020, PMID 31991592 — multicenter cross-sectional GWAS in Mediterranean subjects with metabolic syndrome. In an additive model, each additional C allele at rs174535 was associated with a decrease of 0.339 percentage points in serum omega-3 PUFA (p = 1.49 × 10⁻¹²) and a decrease of 0.111 percentage points in DHA specifically (p = 3.89 × 10⁻¹⁰) — both surpassing the genome-wide significance threshold. The variant was independently replicated in the UK Biobank (N = 188,700), where rs174535 reached p = 1.6 × 10⁻¹² for omega-3 fatty acid levels.

The broader FADS locus context further supports the interpretation. A landmark GWAS of plasma phospholipid PUFAs in 1,075 InCHIANTI participants⁴⁴ A landmark GWAS of plasma phospholipid PUFAs in 1,075 InCHIANTI participants
Tanaka et al. 2009, PLoS Genetics, PMID 19148276 established that variants in this chromosomal region account for up to 18.6% of additive variance in arachidonic acid levels and significantly associate with EPA levels. The CHARGE Consortium meta-analysis (n=8,866)⁵⁵ CHARGE Consortium meta-analysis (n=8,866)
Lemaitre et al. 2011, PLoS Genetics, PMID 21829377 further confirmed that the FADS1/FADS2 haplotype block drives lower circulating EPA and DPA in Europeans.

Practical Actions

For CC homozygotes: lower circulating omega-3 and DHA levels indicate that endogenous PUFA synthesis (whether from MYRF LD effects on FADS activity or from independent mechanisms in the haplotype block) is operating below average capacity. Supplementing with preformed EPA and DHA from marine or algae-based sources bypasses any conversion impairment and directly raises circulating levels. Targeting 2–3 g of combined EPA+DHA daily is appropriate for CC homozygotes.

For CT heterozygotes: one C allele produces a statistically intermediate reduction in omega-3 levels. A daily 1–2 g EPA+DHA supplement from marine fish or algae covers the gap without overcompensating.

Monitoring the omega-3 index (erythrocyte EPA+DHA as % of total fatty acids) provides a direct readout of whether supplementation is achieving the target range (8–12%). This is especially useful for CC carriers to confirm adequacy.

Interactions

rs174535 lies within the same haplotype block as FADS1 rs174537 and FADS1 rs174547 — the two most extensively studied PUFA-associated variants in this region. In individuals who also carry the risk alleles at rs174537 (G allele) or rs174547 (C allele), the combined haplotype may compound the effect on omega-3/DHA levels. Future compound action analyses should evaluate the combined effect of rs174535 CC × rs174537 GG, as both converge on reduced EPA and DHA availability through potentially complementary mechanisms.