rs3798713 — ELOVL2

ELOVL2 rs3798713 — The Last Step Before DHA

Every molecule of DHA in your brain and retina was either eaten directly or assembled through a five-step enzymatic relay starting from alpha-linolenic acid (ALA) in plants. The final, rate-limiting steps of that relay — elongating EPA to DPA, and elongating DPA to the immediate DHA precursor — are both catalysed by a single enzyme: ELOVL2¹¹ ELOVL2
Elongation of Very Long Chain Fatty Acids protein 2, an endoplasmic reticulum enzyme that is the sole C22–C24 elongase in human liver, essential for endogenous DHA biosynthesis. When ELOVL2 is knocked out completely in mice, DHA collapses and DPA accumulates — a fingerprint that matches what is observed in human carriers of ELOVL2 minor alleles. rs3798713 is an intronic variant within ELOVL2 on chromosome 6 that served as the reference marker for the ELOVL2 locus in the largest GWAS of plasma omega-3 levels to date.

The Mechanism

rs3798713 sits within an intron of ELOVL2. Rather than altering the enzyme's amino acid sequence, intronic variants of this type likely act as regulatory elements — tagging haplotypes that influence ELOVL2 gene expression, splicing efficiency, or transcription factor binding at nearby regulatory sites. The rs3798713 C allele is part of a three-SNP haplotype (rs2281591, rs12332786, rs3798713)²² three-SNP haplotype (rs2281591, rs12332786, rs3798713)
This haplotype block in the ELOVL2 gene was associated with linoleic acid concentrations in human breast milk and modulated the PUFA response to dietary DHA intake in a Chinese cohort that associates with altered PUFA processing. The enzymatic consequence is a slowdown at the DPA→24:5n-3→DHA step: DPA accumulates upstream while DHA production is reduced, exactly the pattern observed in both ELOVL2 knockout mice and human GWAS data.

The Evidence

The landmark genetic evidence comes from the CHARGE Consortium meta-analysis³³ CHARGE Consortium meta-analysis
Lemaitre RN et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium. PLoS Genet, 2011, which examined 8,866 European subjects across five cohorts. The ELOVL2 locus — with rs3798713 as the LD reference marker — showed the strongest associations ever reported for a single genetic locus and plasma fatty acid levels: minor alleles associated with higher DPA (p=1×10⁻⁴³), lower DHA (p=1×10⁻¹⁵), and higher EPA (p=2×10⁻¹²). The directionality is diagnostic: upstream metabolites accumulate (EPA, DPA) while the downstream product (DHA) is depleted, pinpointing the block at the final elongation step.

The first GWAS to identify this region, Tanaka et al.⁴⁴ Tanaka et al.
Tanaka T et al. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. PLoS Genet, 2009, independently confirmed the ELOVL2 locus in Italian elderly subjects with replication in the GOLDN cohort.

For omega-3 supplementation, Alsaleh and colleagues⁵⁵ Alsaleh and colleagues
Alsaleh A et al. ELOVL2 gene polymorphisms are associated with increases in plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement. Genes Nutr, 2014 found that ELOVL2 minor allele carriers had lower baseline plasma DHA, yet after 1.8 g/day EPA+DHA supplementation showed approximately 30% higher EPA and 9% higher DHA proportions than non-carriers. This counter-intuitive stronger response — lower baseline but larger gain — is consistent with substrate-driven upregulation of an under-expressed enzyme. A follow-up exploratory study Metherel et al.⁶⁶ Metherel et al.
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. Lipids, 2021 found that the ELOVL2 minor allele also drives pronounced sex differences in how EPA converts to DHA, with female carriers gaining DHA and male carriers losing DHA when given EPA-only supplements.

A Chinese birth cohort study Wu et al.⁷⁷ Wu et al.
Wu Y et al. DHA intake interacts with ELOVL2 and ELOVL5 genetic variants to influence polyunsaturated fatty acids in human milk. J Lipid Res, 2019 confirmed a gene-diet interaction in breast milk: carriers of the rs3798713 haplotype who consumed higher dietary DHA showed elevated concentrations of LA, AA, EPA, and DHA in milk — suggesting that adequate DHA intake partially compensates for the reduced elongation efficiency.

Practical Actions

The ELOVL2 locus has unusually large effect sizes for a common variant, explaining a meaningful fraction of population variation in plasma DHA. For C allele carriers, the implication is direct: endogenous DHA synthesis through the ALA→EPA→DPA→DHA pathway is less efficient. Plant-based omega-3 sources (flaxseed, chia, walnuts) supply ALA, which must traverse this impaired elongation step. Marine-sourced EPA and DHA from fatty fish, fish oil, or algae supplements bypass the bottleneck by delivering the end-product directly.

The gene-diet interaction observed by Wu et al. supports this: increasing dietary DHA intake materially improves PUFA status in C allele carriers, consistent with substrate loading partially compensating for reduced enzyme efficiency.

Interactions

rs3798713 is in the same ELOVL2 gene as rs17606561, rs953413, rs2236212, and rs3734398. These variants may be in linkage disequilibrium and their effects on DHA metabolism are likely partially overlapping. Carrying risk alleles across multiple ELOVL2 SNPs would represent cumulative impairment of the same enzyme.

ELOVL2 operates downstream of FADS1 and FADS2 desaturases in the omega-3 cascade. FADS1 variants (rs174547) and FADS2 variants (rs174537) reduce the supply of EPA that ELOVL2 then elongates. Carriers of impaired alleles in both FADS and ELOVL2 have a double bottleneck: less EPA substrate entering the elongation step, combined with reduced elongation efficiency at the ELOVL2 step. This combination has the strongest rationale for relying entirely on preformed marine DHA rather than plant precursors.