Single nucleotide polymorphisms in the FADS gene cluster are associated with delta-5 and delta-6 desaturase activities estimated by serum fatty acid ratios

Abstract

Genetic variability in the FADS1-FADS2 gene cluster [encoding delta-5 (D5D) and delta-6 (D6D) desaturases] has been associated with plasma long-chain PUFA (LCPUFA) and lipid levels in adults. To better understand these relationships, we further characterized the association between FADS1-FADS2 genetic variability and D5D and D6D activities in adolescents. Thirteen single nucleotide polymorphisms (SNPs) were genotyped in 1,144 European adolescents (mean +/- SD age: 14.7 +/- 1.4 y). Serum phospholipid fatty acid levels were analyzed using gas chromatography. D5D and D6D activities were estimated from the C20:4n-6/C20:3n-6 and C20:3n-6/C18:2n-6 ratios, respectively. Minor alleles of nine SNPs were associated with higher 18:2n-6 levels (1.9E-18 <or= P <or= 6.1E-5), lower C20:4n-6 levels (7.1E-69 <or= P <or= 1.2E-12), and lower D5D activity (7.2E-44 <or= P <or= 4.4E-5). All haplotypes carrying the rs174546 minor allele were associated with lower D5D activity, suggesting that this SNP is in linkage disequilibrium with a functional SNP within FADS1. In contrast, only the rs968567 minor allele was associated with higher D6D activity (P = 1.5E-6). This finding agrees with an earlier in vitro study showing that the minor allele of rs968567 is associated with a higher FADS2 promoter activity. These results suggest that rare alleles of several SNPs in the FADS gene cluster are associated with higher D6D activity and lower D5D activity in European adolescents.

Figures

Fig. 1.

Pathways for LCPUFA synthesis from n-6 and n-3 essential FAs. ALA: α-linoleic acid; ARA: arachidonic acid; DGLA: dihomo-γ-linoleic acid; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; GLA: γ-linoleic acid; LA: linoleic acid; SA: stearidonic acid.

Fig. 2.

Structure of the FADS gene cluster and linkage disequilibrium patterns for the 13 investigated FADS SNPs. The red scale is for D’ values and numbers are for r2 values. Only the rs498793 SNP is in negative linkage disequilibrium (D’<0) with the others.

Fig. 3.

Association of FADS genotypes with variations in n-6 LCPUFA levels (%). In each graph and for each SNP, the first bar represents the reference value [the mean level (± SD) of the n-6 LCPUFA in homozygotes for the major allele]. The second and third bars indicate the n-6 LCPUFA level in heterozygote and homozygotes for the minor allele, respectively, calculated as a percentage of the reference value. White and black bars represent heterozygotes and homozygotes, respectively. All tests were adjusted for age, gender, BMI, and center. Significant associations (P < 0.0003) are indicated by boxes around the SNP.

Fig. 4.

Association of FADS genotypes with variations in n-3 LCPUFA levels (%). In each graph and for each SNP, the first bar represents the reference value [the mean level (±SD) of the n-3 LCPUFA in homozygotes for the major allele]. The second and third bars indicate the n-3 LCPUFA level in heterozygote and homozygotes for the minor allele, respectively, calculated as a percentage of the reference value. White and black bars represent heterozygotes and homozygotes, respectively. All tests were adjusted for age, gender, BMI, and center. Significant associations (P < 0.0003) are indicated by boxes around the SNP.