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.
Highlights
Essential fatty acids are important constituents of all cell membranes and influence both inflammatory and atherosclerotic processes
Significant associations of fatty acid desaturase 1 (FADS1), FADS2, and CPT1A transcripts with their respective single-nucleotide polymorphisms (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 erythrocyte D5D (eD5D) activity
Recent genome-wide association studies (GWAS) have shown a strong association between polyunsaturated fatty acids (PUFAs) and single-nucleotide polymorphisms (SNPs) in fatty acid desaturase 1 and 2 (FADS1 and FADS2) genes, which code for D5D and D6D, www.frontiersin.org
Summary
Essential fatty acids are important constituents of all cell membranes and influence both inflammatory and atherosclerotic processes. Increased activities of these desaturases could stimulate the synthesis of EPA (which has anti-inflammatory properties) from ALA, counteracting the effects of AA synthesis. Both EPA and AA are synthesized at very low rates in vivo (Harris et al, 2009; Mozaffarian et al, 2010). Metabolism, and genetic variation influence the fatty acid composition of the plasma lipids and cell membranes. The variation in plasma and dietary fatty acids, polyunsaturated fatty acids (PUFAs), has been shown to be under considerable genetic influence (Cai et al, 2004; Tanaka et al, 2009; Voruganti et al, 2010). Recent genome-wide association studies (GWAS) have shown a strong association between PUFAs and single-nucleotide polymorphisms (SNPs) in fatty acid desaturase 1 and 2 (FADS1 and FADS2) genes, which code for D5D and D6D, www.frontiersin.org
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