Variants in CPT1A, FADS1, and FADS2 are Associated with Higher Levels of Estimated Plasma and Erythrocyte Delta-5 Desaturases in Alaskan Eskimos

Abstract

The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes, respectively, are rate-limiting enzymes in the metabolism of ω-3 and ω-6 fatty acids. The objective of this study was to identify genes influencing variation in estimated D5D and D6D activities in plasma and erythrocytes in Alaskan Eskimos (n = 761) participating in the genetics of coronary artery disease in Alaska Natives (GOCADAN) study. Desaturase activity was estimated by product: precursor ratio of polyunsaturated fatty acids. We found evidence of linkage for estimated erythrocyte D5D (eD5D) on chromosome 11q12-q13 (logarithm of odds score = 3.5). The confidence interval contains candidate genes FADS1, FADS2, 7-dehydrocholesterol reductase (DHCR7), and carnitine palmitoyl transferase 1A, liver (CPT1A). Measured genotype analysis found association between CPT1A, FADS1, and FADS2 single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (p-values between 10(-28) and 10(-5)). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in CPT1A, rs174541 in FADS1, and rs174568 in FADS2 had posterior probabilities > 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of FADS1, FADS2, and CPT1A transcripts with their respective SNPs (p-values between 10(-75) and 10(-7)) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for FADS1, FADS2, and CPT1A SNPs in the variation in eD5D activity.

Keywords: bayesian quantitative trait nucleotide analysis; essential fatty acids; single-nucleotide polymorphisms.

Figure 1

Metabolism of essential fatty acids.

Figure 2

Genome-wide linkage analysis for erythrocyte D5D localizes a QTL on chromosome 11. The QTL for plasma and erythrocyte D5D estimates on chromosome 11. Solid line, erythrocyte D5D (LOD = 3.5 at 82 cM); dashed line, plasma D5D (LOD = 0.9 at 81 cM).

Figure 3

Manhattan plots showing the association of SNPs on CPT1A and FADS1 and FADS2 with erythrocyte D5D. (A) CPT1A and (B) FADS1and FADS2.

Figure 4

Conditional linkage analysis for erythrocyte D5D on chromosome 11. Linkage analysis conditional on the most significantly associated SNP in (A) CPT1A, (B) FADS1, and (C) FADS2. Solid line, erythrocyte D5D; dashed line, erythrocyte D5D conditional on SNPs.