rs953413 — ELOVL2

Intronic enhancer variant in ELOVL2 that controls transcription factor binding to the ELOVL2 promoter, with the A allele reducing elongase-2 expression and impairing EPA-to-DHA conversion; the lead InCHIANTI GWAS signal for plasma EPA levels and a modifier of sex-specific DHA response to omega-3 supplementation

See your personal result for ELOVL2

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

ELOVL2 rs953413 — The Enhancer Switch for DHA Synthesis

The conversion of dietary plant omega-3s into DHA — the brain's dominant structural fat — is governed by a chain of enzymes whose efficiency varies widely between individuals. ELOVL2 (elongase of very long chain fatty acids protein 2) catalyzes the critical elongation step that converts EPA (20:5) into DPA (22:5) and then toward DHA (22:6). The rs953413 variant, sitting in the first intron of ELOVL2, controls how much of this enzyme the liver makes. Unlike many GWAS variants whose functional mechanism remains unknown, rs953413 has a precisely characterized molecular role: it sits inside a cooperative enhancer element11 cooperative enhancer element
A regulatory DNA sequence that increases transcription of a nearby gene when transcription factors bind to it that is bound by the liver transcription factors FOXA1/FOXA2 and HNF4α22 FOXA1/FOXA2 and HNF4α
Hepatocyte nuclear factors — master regulators of liver gene expression that coordinate fatty acid, glucose, and bile acid metabolism.

The Mechanism

Pan and colleagues33 Pan and colleagues
Pan G et al. rs953413 Regulates Polyunsaturated Fatty Acid Metabolism by Modulating ELOVL2 Expression. iScience, 2020 used luciferase reporter assays, ChIP-qPCR, and CRISPR/Cas9 editing in hepatic cell lines to show that the G allele of rs953413 preferentially recruits FOXA1, FOXA2, and HNF4α to an evolutionarily conserved intronic enhancer. This allele-specific transcription factor binding upregulates ELOVL2 expression. The A allele disrupts this binding, reducing ELOVL2 transcription. FOXA knockdown and direct Cas9 mutation of the enhancer both significantly downregulated ELOVL2 expression (p < 0.01), confirming the causal chain from SNP → transcription factor binding → ELOVL2 expression → LC-PUFA levels.

The downstream consequence is that A-allele carriers produce less ELOVL2 enzyme, slowing the EPA→DPA→DHA elongation cascade in the liver. This creates a phenotype with characteristically lower baseline DHA but paradoxically greater responsiveness to preformed omega-3 supplementation — a pattern seen across multiple independent intervention trials.

The Evidence

rs953413 was the lead variant in the original InCHIANTI GWAS44 InCHIANTI GWAS
Tanaka T et al. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet, 2009 of 1,075 Italian adults, where it reached p = 1.1×10⁻⁶ for plasma EPA — establishing ELOVL2 as a major genetic determinant of omega-3 fatty acid levels in humans. The signal replicated in 1,076 GOLDN study participants, where ELOVL2 variants were associated with DPA and DHA levels.

The most striking clinical data comes from an exploratory supplementation trial by Metherel and colleagues55 Metherel and colleagues
Metherel AH et al. Higher Increase in Plasma DHA in Females Compared to Males Following EPA Supplementation May Be Influenced by a Polymorphism in ELOVL2: An Exploratory Study. Lipids, 2021. Young adults (n = 14–15 per group) received 3 g/day EPA for 12 weeks. Overall, females showed substantially greater plasma DHA increases than males (+23.8 vs. −13.8 nmol/mL; p < 0.01). When stratified by rs953413 genotype, the effect was dramatic: AA-genotype females gained +58.8 ± 11.5 nmol/mL DHA, compared to +4.34 ± 13.5 nmol/mL for GA+GG females and −29.1 ± 17.2 nmol/mL for AA males (p < 0.001). This sex × genotype interaction suggests that estrogen-mediated upregulation of the EPA→DHA elongation pathway partially compensates for the low-ELOVL2 A-allele phenotype in females, while AA-genotype males face the full deficit.

The Alsaleh 2014 fish oil trial66 Alsaleh 2014 fish oil trial
Alsaleh A et al. ELOVL2 gene polymorphisms are associated with increases in plasma EPA and DHA proportions after fish oil supplement. Genes Nutr, 2014 of 367 subjects confirmed that ELOVL2 minor-allele carriers — across rs953413, rs2236212, and rs3734398 — showed approximately 30% higher plasma EPA and 9% higher DHA after 1.8 g/day fish oil supplementation (p = 0.002–0.017), reinforcing that preformed omega-3 supply strongly compensates for reduced endogenous elongation.

A notable additional dimension of this locus is its role in epigenetic aging77 epigenetic aging
DNA methylation changes that accumulate with age and can be used to predict biological age independently of chronological age. Garagnani and colleagues88 Garagnani and colleagues
Garagnani P et al. Methylation of ELOVL2 gene as a new epigenetic marker of age. Aging Cell, 2012 demonstrated that CpG island methylation in the ELOVL2 promoter/enhancer region correlates with chronological age at r = 0.92 across 501 subjects aged 9–99 years. The rs953413 variant sits within precisely this regulatory region. Whether the SNP's effect on transcription factor binding modulates the rate of age-associated methylation accumulation remains an open research question, but the overlap establishes this locus as a convergence point for fatty acid metabolism and biological aging biology.

Practical Implications

For AA-genotype individuals, the key implications are: (1) endogenous DHA synthesis from plant-derived ALA or EPA is constrained by reduced ELOVL2 activity; (2) preformed DHA supplementation bypasses this bottleneck and is well-supported by multiple intervention studies; (3) males with AA are at greater deficit than females because estrogen-mediated elongation partially compensates in women. Fish oil or algae-based DHA at 1–2 g/day is the most direct intervention, with the omega-3 index as the objective measure of adequacy.

Interactions

rs953413 is in partial linkage disequilibrium with rs2236212 in European populations, and both variants affect ELOVL2 activity through different mechanisms: rs2236212 is associated with reduced enzymatic elongation activity (Maguolo et al. 2021), while rs953413 acts upstream by controlling transcription factor binding and ELOVL2 gene expression. Carrying risk alleles at both loci may compound the reduction in DHA synthesis capacity. Upstream in the same pathway, FADS1/FADS2 variants (rs174547, rs174537) affect the desaturation of ALA to EPA — individuals with both FADS low-activity and ELOVL2 low-expression genotypes face impairment at two sequential steps, making plant-based omega-3 strategies essentially ineffective and preformed marine DHA the only reliable route to adequate status.

Nutrient Interactions

DHA (docosahexaenoic acid) impaired_conversion
EPA (eicosapentaenoic acid) altered_metabolism
omega-3 fatty acids increased_need

Genotype Interpretations

What each possible genotype means for this variant.

GG High ELOVL2 Expression Normal

Full ELOVL2 enhancer activity — efficient EPA-to-DHA elongation

With two G alleles, your rs953413 enhancer element supports optimal FOXA and HNF4α binding, producing normal ELOVL2 enzyme levels. The elongation cascade — EPA (20:5) → DPA (22:5) → DHA (22:6) — proceeds efficiently in the liver. Your DHA status reflects primarily dietary intake rather than a genetically imposed synthesis ceiling.

Standard dietary sources of EPA and DHA (fatty fish 2–3× per week or 500 mg/day supplementation) are appropriate for maintenance. You are not specifically disadvantaged by this locus relative to omega-3 metabolism.

AG Reduced ELOVL2 Expression Intermediate

Moderately reduced ELOVL2 enhancer activity — partial DHA synthesis impairment

With one A and one G allele, you have one functional copy of the rs953413 enhancer and one reduced-activity copy. This produces intermediate ELOVL2 expression and intermediate elongation efficiency. Baseline plasma DHA may trend lower than GG individuals, particularly when marine food intake is low.

The Alsaleh 2014 trial and Medoro 2025 study both found that A-allele carriers (including heterozygotes) showed greater plasma EPA and DHA increases per gram of fish oil supplemented, consistent with a supply-limited elongation bottleneck that is partially relieved by providing preformed substrates. This means supplementation is both more necessary and more effective compared to GG individuals.

AA Low ELOVL2 Expression Reduced

Substantially reduced ELOVL2 enhancer activity — impaired DHA synthesis, especially in males

With two A alleles, both copies of your ELOVL2 enhancer have disrupted transcription factor binding. Pan et al. 2020 showed that the A allele significantly reduces FOXA1/FOXA2 and HNF4α binding (p < 0.01), downregulating ELOVL2 expression in hepatic cells. The functional consequence is that the elongation cascade EPA → DPA → DHA is substantially slowed.

The sex difference is clinically important (Metherel et al. 2021, PMID 33174255). Females with AA genotype achieved +58.8 nmol/mL DHA after 3 g/day EPA supplementation because estrogen appears to independently upregulate EPA elongation via other pathways, partially compensating for the ELOVL2 deficit. Males with AA genotype, lacking this estrogen-mediated compensation, showed net DHA loss (−29.1 nmol/mL) with EPA supplementation — meaning males with AA specifically need preformed DHA rather than EPA-only supplements to raise plasma DHA.

Plant-based omega-3 strategies (flaxseed, chia, walnuts) that rely on ALA → EPA → DHA conversion are particularly ineffective for AA individuals: both the ALA → EPA step (requiring FADS2) and the EPA → DHA step (requiring ELOVL2) must work efficiently for plant ALA to reach DHA. The ELOVL2 bottleneck at the second step makes plant ALA an unreliable DHA source regardless of FADS2 status.

The rs953413 variant sits within the ELOVL2 promoter/enhancer region that also shows the strongest age-associated methylation increase of any locus in the human genome (r = 0.92 with age; Garagnani et al. 2012). This convergence — a genetic variant that reduces ELOVL2 expression sitting in the region that also undergoes the most rapid age-related silencing — may make AA individuals particularly vulnerable to declining DHA synthesis as they age.