Genetic variation at the FADS1-FADS2 gene locus influences delta-5 desaturase activity and LC-PUFA proportions after fish oil supplement

Abstract

Delta-5 and delta-6 desaturases (D5D and D6D) are key enzymes in endogenous synthesis of long-chain PUFAs. In this sample of healthy subjects (n = 310), genotypes of single nucleotide polymorphisms (SNPs) rs174537, rs174561, and rs3834458 in the FADS1-FADS2 gene cluster were strongly associated with proportions of LC-PUFAs and desaturase activities estimated in plasma and erythrocytes. Minor allele carriage associated with decreased activities of D5D (FADS1) (5.84 × 10(-19) ≤ P ≤ 4.5 × 10(-18)) and D6D (FADS2) (6.05 × 10(-8) ≤ P ≤ 4.20 × 10(-7)) was accompanied by increased substrate and decreased product proportions (0.05 ≤ P ≤ 2.49 × 10(-16)). The significance of haplotype association with D5D activity (P = 2.19 × 10(-17)) was comparable to that of single SNPs, but haplotype association with D6D activity (P = 3.39 × 10(-28)) was much stronger. In a randomized controlled dietary intervention, increasing eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) intake significantly increased D5D (P = 4.0 × 10(-9)) and decreased D6D activity (P = 9.16 × 10(-6)) after doses of 0.45, 0.9, and 1.8 g/day for six months. Interaction of rs174537 genotype with treatment was a determinant of D5D activity estimated in plasma (P = 0.05). In conclusion, different sites at the FADS1-FADS2 locus appear to influence D5D and D6D activity, and rs174537 genotype interacts with dietary EPA+DHA to modulate D5D.

Fig. 1.

Pathways for LC-PUFA synthesis from n-6 and n-3 essential fatty acids. The synthesis of n-6 LC-PUFAs from LA and n-3 from ALA proceeds in parallel by alternating actions of elongases and desaturases. Analyzed LC-PUFAs are shown in bold.

Fig. 2.

Pairwise linkage disequilibrium D′ and r² plots of the three common SNPs in the MARINA study participants (n = 282). The positions in bp for rs174537, rs174561, and rs3834458 on chromosome 11 are shown. Derived from NCBI HapMap Data Release 28 Phase II+III August 2010.

Fig. 3.

Association between rs174537 and D5D activity stratified by intake of EPA+DHA. D5D activity was estimated by ratio of (AA:DGLA) (20:4n-6:20:3n-6) in (A) plasma (n = 284) and (B) erythrocytes (n = 286). Carriers of the minor T-allele had lower D5D activity estimated from ratio in plasma (P = 0.05) and erythrocytes (P = 6.96 × 10⁻⁷) compared with GG in the placebo group (n = 65 plasma, n = 66 erythrocytes). After treatment, D5D activity showed a significant increase with dosage in T-allele carriers (P = 3.2 × 10⁻¹⁰ in plasma and P = 4.3 × 10⁻⁴ in erythrocytes), but not in GG homozygotes (P = 0.11 and P = 0.76, respectively). Interaction between genotype and dosage as a determinant of D5D activity determined by univariate ANOVA, yielding P values uncorrected for multiple comparisons, was significant at P < 0.05 (P = 0.05 plasma; P = 0.02 erythrocytes). Interaction determined by multivariate ANOVA, yielding P values corrected for multiple comparisons, remained significant for the plasma estimate (P = 0.05) but not for the erythrocyte measure (P = 0.20).