Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study

Abstract

Polyunsaturated fatty acids (PUFA) have a role in many physiological processes, including energy production, modulation of inflammation, and maintenance of cell membrane integrity. High plasma PUFA concentrations have been shown to have beneficial effects on cardiovascular disease and mortality. To identify genetic contributors of plasma PUFA concentrations, we conducted a genome-wide association study of plasma levels of six omega-3 and omega-6 fatty acids in 1,075 participants in the InCHIANTI study on aging. The strongest evidence for association was observed in a region of chromosome 11 that encodes three fatty acid desaturases (FADS1, FADS2, FADS3). The SNP with the most significant association was rs174537 near FADS1 in the analysis of arachidonic acid (AA; p = 5.95 x 10(-46)). Minor allele homozygotes had lower AA compared to the major allele homozygotes and rs174537 accounted for 18.6% of the additive variance in AA concentrations. This SNP was also associated with levels of eicosadienoic acid (EDA; p = 6.78 x 10(-9)) and eicosapentanoic acid (EPA; p = 1.07 x 10(-14)). Participants carrying the allele associated with higher AA, EDA, and EPA also had higher low-density lipoprotein (LDL-C) and total cholesterol levels. Outside the FADS gene cluster, the strongest region of association mapped to chromosome 6 in the region encoding an elongase of very long fatty acids 2 (ELOVL2). In this region, association was observed with EPA (rs953413; p = 1.1 x 10(-6)). The effects of rs174537 were confirmed in an independent sample of 1,076 subjects participating in the GOLDN study. The ELOVL2 SNP was associated with docosapentanoic and DHA but not with EPA in GOLDN. These findings show that polymorphisms of genes encoding enzymes in the metabolism of PUFA contribute to plasma concentrations of fatty acids.

Figure 1. The metabolic pathway of n-3 and n-6 fatty acids.

The fatty acids examined in the study are indicated in bold. The dashed arrows indicate pathways absent in mammals.

Figure 2. Genome-wide scans of omega-6 fatty acid profiles in InCHIANTI study.

Genome-wide associations of plasma linoleic acid (A), eicasadienoic acids (B) and arachidonic acid (C) with 495,343 autosomal and X chromosome SNPs that passed quality control graphed by chromosome position and −log10 p-value. The most significant variant was within the FAD1/FAD2/FAD3 cluster on chromosome 11. The genes nearby or within the SNPs that were selected for replication in GOLDN are indicated.

Figure 3. Genome-wide scans of omega-3 fatty acid profiles in InCHIANTI study.

Genome-wide associations of plasma alpha linolenic acid (A), eicosapentanoic acid (B) and docasahexanoic acid (C) with 495,343 autosomal and X chromosome SNPs that passed quality control graphed by chromosome position and −log10 p-value. The most significant variant was within the FAD1/FAD2/FAD3 cluster on chromosome 11. The genes nearby or within the SNPs that were selected for replication in GOLDN are indicated.