Variants in CPT1A, FADS1, and FADS2 are Associated with Higher Levels of Estimated Plasma and Erythrocyte Delta-5 Desaturases in Alaskan Eskimos.
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.
Department of Genetics, Texas Biomedical Research Institute San Antonio, TX, USA.
V Saroja
VS
Voruganti
Paul B
PB
Higgins
Sven O E
SO
Ebbesson
John
J
Kennish
Harald H H
HH
Göring
Karin
K
Haack
Sandra
S
Laston
Eugene
E
Drigalenko
Charlotte R
CR
Wenger
William S
WS
Harris
Richard R
RR
Fabsitz
Richard B
RB
Devereux
Jean W
JW
Maccluer
Joanne E
JE
Curran
Melanie A
MA
Carless
Matthew P
MP
Johnson
Eric K
EK
Moses
John
J
Blangero
Jason G
JG
Umans
Barbara V
BV
Howard
Shelley A
SA
Cole
Anthony Gean
AG
Comuzzie