FADS genetic variants and omega-6 polyunsaturated fatty acid metabolism in a homogeneous island population

Abstract

Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and inflammation through their capacity to be converted to potent inflammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and five ratios defining FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) (P = 5.8 x 10(-7) - 1.7 x 10(-8)) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the omega-6 series (P = 2.11 x 10(-13) - 1.8 x 10(-20)). The minor allele across all SNPs was consistently associated with decreased omega-6 PUFAs, with the exception of dihomo-gamma-linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our findings in a geographically isolated population with a homogenous dietary environment suggest that variants in the Delta-5 desaturase enzymatic step likely regulate the efficiency of conversion of medium-chain PUFAs to potentially inflammatory PUFAs, such as AA.

Fig. 1.

Biosynthetic pathway of ω3 and ω6 polyunsaturated fatty acids (PUFAs). Fatty acids are obtained from the diet or by de novo FA synthesis (upper left), which builds saturated fatty acids (SFA) by 2-carbon unit increments to the 18-carbon stearic acid (C18:0; i.e., 18 carbons with no double bonds) and takes place in all organisms. Stearoyl coenzyme A desaturase 1(SCD1) initiates fatty acid desaturation and generates the precursors of the ω-7 and ω-9 series fatty acids (upper left). The lack of Δ-12 and Δ-15 desaturase (dashed box) in animals renders linoleic acid (LA) and α-linolenic acid (ALA) essential fatty acids (^**) and thus must be obtained from the diet, generally from plant-derived sources. The synthesis of ω-9 (derived from oleic acid, 18:1ω9; series not shown), ω-6 (from LA, 18:2ω6) and ω-3 (from ALA, 18:3ω) PUFAs proceeds in parallel, with the activity of Δ-6 desaturase (FADS2) thought to be the rate-limiting step in PUFA synthesis. In animals and organisms at the base of the food chain, LC-PUFAs are synthesized by alternating actions of elongases (red arrows) and desaturases (blue arrows). In mammals, a variety of enzymes (green arrows) generate numerous bioactive derivatives from ω-6 (DHGLA and AA) and ω-3 (EPA, DHA) PUFAs that have numerous targets and functions throughout the body. With the exception of the series-1 prostaglandins (PG), thromboxanes (TX), and leukotrienes (LT) derived from DHGLA, the ω6-derived lipid mediators (series-2 and -4) tend to have proinflammatory actions. Like the series-1 lipid mediators, the series-3 and -5 metabolites of ω3 PUFAs generally exhibit less inflammatory to anti-inflammatory properties. AA, arachidonic acid; DHGLA, dihomo-gamma-linolenic acid; EPA, eicosapentanoic acid; FADS, fatty acid desaturase.

Fig. 2.

Physical location (A) of the 16 SNPs and the gene structure of the FADS gene cluster are shown (dark blue line = physical location of genotyped SNP; light blue/pink boxes = exon/intron structure with FADS genes). Schematic overview of linkage disequilibrium patterns (B) in the 102 kb region containing the FADS gene cluster (Chr 11 q12-13), as defined by the algorithm of Gabriel et al. (31) using 224 subjects in the analysis (range of LD from high to low displayed as color ranging from dark red to white, respectively). Abbreviations: FADS, fatty acid desaturase; SNP, single nucleotide polymorphism.

Fig. 3.

A schematic overview of association analyses for 16 SNPs in the FADS gene cluster and PUFAs (N = 10) and PUFA ratios (N = 5) in 224 subjects from the Tangier population. The ratios included are (i) enzymatic activity in the total pathway in ω6 series (TPω6) defined as (AA+ADA)/(LA+GLA+DHGLA); (ii) enzymatic activity in the total pathway in ω3 series (TPω3) defined as (EPA+DPA)/(ALA+SDA+ETEA); (iii) Fatty acid desaturase 1 (FADS1) activity in the ω6 series (FADS1ω6) defined as (AA+ADA)/DHGLA; (iv) FADS1 activity in the ω3 series (FADS1ω3) defined as (EPA+DPA)/ETEA; and (v) FADS2 activity in the ω6 series (GLA/LA). The P values of these association tests are shown in Panel A, and the specific allele associated with an increased mean trait value for each phenotype is shown in Panel B for all tests, where P < 0.05. Color key mapping P values and alleles to specific color codes are displayed. Abbreviations: AA, arachidonic acid; ADA, adrenic acid; ALA, alpha-linolenic acid; DHGLA, dihomo-gamma-linolenic acid; DPA, docosapentaenoic acid; EPA, eicosapentanoic acid; ETEA, eicosatetraenoic acid; FADS, fatty acid desaturase; GLA, gamma-linolenic acid; LA, linoleic acid; PUFA, polyunsaturated fatty acid; SNP, single nucleotide polymorphism.

Fig. 4.

Phenotypic distributions of AA (top panel, product of FADS1), DHGLA (middle panel, substrate of FADS1), and FADS1ω6 (bottom panel, FADS1 activity in the ω6 series) by the three genotypes at SNP rs174537) in 224 subjects from the Tangier population. In each panel (1), a frequency distribution of the full distribution of the phenotype (N = 224) is shown in black boxes (2); the histogram of the distribution in the subjects with the GG genotype (N = 107) in a green line (3); the histogram of the distribution in the subjects with the GT heterozygote genotype (N = 83) in a blue line; and (4) the histogram of the distribution in the subjects with the TT homozygote genotype (N = 21) in a red line. Abbreviations: AA, arachidonic acid; DHGLA, dihomo-gamma-linolenic acid; FADS, fatty acid desaturase; SNP, single nucleotide polymorphism.