AUTHOR=Voruganti V. Saroja , Higgins Paul B., Ebbesson Sven O., kennish John , Goring Harald H., Haack Karin , Laston Sandra , Drigalenko Eugene , Wenger Charlotte R., Harris William , Fabsitz Richard R., Devereux Richard B., MacCluer Jean , Curran Joanne , Carless Melanie , Johnson Matthew , Moses Eric , Blangero John , Umans Jason G., Howard Barbara V., Cole Shelley , Comuzzie Anthony G.

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

JOURNAL=Frontiers in Genetics

VOLUME=3

YEAR=2012

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2012.00086

DOI=10.3389/fgene.2012.00086

ISSN=1664-8021

ABSTRACT=<p>The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (<italic>FADS1</italic>) and 2 (<italic>FADS2</italic>) 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 (<italic>n</italic> = 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 <italic>FADS1</italic>, <italic>FADS2</italic>, 7-dehydrocholesterol reductase (<italic>DHCR7</italic>), and carnitine palmitoyl transferase 1A, liver (<italic>CPT1A</italic>). Measured genotype analysis found association between <italic>CPT1A</italic>, <italic>FADS1</italic>, and <italic>FADS2</italic> single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (<italic>p</italic>-values between 10<sup>−28</sup> and 10<sup>−5</sup>). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in <italic>CPT1A</italic>, rs174541 in <italic>FADS1</italic>, and rs174568 in <italic>FADS2</italic> had posterior probabilities &gt; 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of <italic>FADS1</italic>, <italic>FADS2</italic>, and <italic>CPT1A</italic> transcripts with their respective SNPs (<italic>p</italic>-values between 10<sup>−75</sup> and 10<sup>−7</sup>) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for <italic>FADS1</italic>, <italic>FADS2</italic>, and <italic>CPT1A</italic> SNPs in the variation in eD5D activity.</p>