rs968567 — FADS2 FADS2 Promoter D6D Activity Variant

FADS2 rs968567 — The Promoter Dial for Delta-6 Desaturase

Most genetic variants in the FADS gene cluster reduce enzyme activity. rs968567 works differently: the minor T allele turns up delta-6 desaturase (D6D¹¹ D6D
FADS2 — the enzyme that adds a double bond at the sixth carbon position, the rate-limiting first step in converting dietary linoleic acid to GLA and alpha-linolenic acid to stearidonic acid). Instead of blocking PUFA synthesis, T allele carriers push the omega-6 and omega-3 pathways faster — generating more downstream products from dietary precursors. The consequences are nuanced: accelerated conversion boosts EPA production from plant ALA, but also drives more arachidonic acid from omega-6 sources, with opposing effects on inflammatory signalling depending on dietary context.

The Mechanism

rs968567 sits in the promoter region of FADS2 on chromosome 11 (position 61,828,092, GRCh38). The critical molecular finding²² critical molecular finding
Lattka et al. A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1. J Lipid Res, 2010 is that the T allele creates a binding site for ELK1, a member of the ETS transcription factor family. When ELK1 binds, it drives higher FADS2 mRNA transcription. The C allele does not create this binding site, leaving D6D expression at its baseline. Luciferase reporter assays across three cell lines confirmed allele-dependent differences in promoter activity, establishing rs968567 as a functional, mechanistically-explained regulatory variant — not simply a tag for a nearby causal site.

D6D catalyses two parallel reactions: (1) linoleic acid (LA, the dominant dietary omega-6) → gamma-linolenic acid (GLA) → DGLA → arachidonic acid (AA); (2) alpha-linolenic acid (ALA, the plant omega-3) → stearidonic acid (SDA) → eicosatetraenoic acid (ETA) → EPA. Higher D6D activity in T allele carriers means both pathways run faster from the same precursor intake, but whether that produces a net benefit or a net risk depends critically on the ratio of omega-6 to omega-3 in the diet.

The Evidence

The functional promoter finding was validated physiologically in the HELENA study³³ HELENA study
Bokor et al. Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios. J Lipid Res, 2010 — 1,144 European adolescents across seven countries. Of all FADS2 SNPs tested, rs968567 was the only one specifically and significantly associated with higher estimated D6D activity (p=1.5×10⁻⁶). This directly connects the ELK1-driven promoter upregulation seen in cell assays to measurable enzyme activity variation in living humans.

The effect extends to the earliest stage of human development. In the ALSPAC birth cohort⁴⁴ ALSPAC birth cohort
Lattka et al. Umbilical cord PUFA are determined by maternal and child fatty acid desaturase (FADS) genetic variants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Br J Nutr, 2013, analysing >2,000 mother-child pairs, rs968567 was one of only two FADS2 variants with specific, independent effects on umbilical cord plasma PUFA composition. This means D6D activity differences from rs968567 are not a post-natal diet interaction — they shape fetal fatty acid availability during development.

The net effect on circulating fatty acids in healthy young adults⁵⁵ healthy young adults
Roke et al. Variation in the FADS1/2 gene cluster alters plasma n-6 PUFA. Prostaglandins Leukot Essent Fatty Acids, 2013 follows predictably: FADS gene cluster minor allele carriers (including rs968567 T allele carriers) showed lower circulating AA and reduced desaturase indices. This appears paradoxical given the T allele elevates D6D — but the explanation lies in genetic LD: rs968567 T allele tags a haplotype that, across the cluster, tracks with different product ratios than the isolated promoter effect would predict. The promoter activity study and the desaturase index study together frame the actual phenotype: elevated D6D at rs968567 specifically shifts flux through both pathways, but the net plasma AA outcome depends on the full FADS haplotype background.

Practical Actions

The key dietary implication of elevated D6D activity is that the balance between omega-6 and omega-3 precursor intake matters more than for people with baseline D6D. T allele carriers convert LA to AA more efficiently: on a Western diet high in linoleic acid (from vegetable oils, processed foods), this produces more arachidonic acid and its pro-inflammatory eicosanoids. The same elevated D6D also converts ALA to SDA and further to EPA more efficiently — meaning T allele carriers are better responders to plant-based omega-3 sources, and better responders to EPA/DHA supplementation when baseline intake is adequate.

The practical priority is managing the omega-6 load specifically — reducing high-LA vegetable oils (soybean, sunflower, corn oil) and replacing with low-LA alternatives (olive oil, macadamia oil, avocado oil) directly limits the AA overproduction that elevated D6D can drive.

Interactions

rs968567 sits on chromosome 11q12.2 in proximity to the broader FADS1/FADS2/FADS3 gene cluster. The promoter variant acts upstream of the FADS2 coding sequence; coding or intronic variants in the same gene (rs174568, rs174575, rs174553) that reduce D6D expression can partially offset the T allele's upregulation effect when co-inherited on the opposite haplotype. For users with both rs968567 T allele and a FADS1 reduced-activity variant (such as rs174541 or rs174547), the downstream pathway is complex: FADS2 elevates EPA substrate supply via faster ALA conversion, but the impaired FADS1 delta-5 step still limits the final EPA yield. The net omega-3 status in this combination depends on both steps — supplementing with preformed EPA/DHA remains the most reliable strategy regardless of which FADS enzyme is rate-limiting.