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J Clin Lipidol. 2018 Mar - Apr;12(2):311-320.e3. doi: 10.1016/j.jacl.2017.10.020. Epub 2017 Nov 2.

A common variant in ARHGEF10 alters delta-6 desaturase activity and influence susceptibility to hypertriglyceridemia.

Author information

1
Institute of Nutrition and Functional Foods (INAF), Laval University, Quebec City, QC, Canada; School of Nutrition, Laval University, Quebec City, QC, Canada.
2
Endocrinology and Nephrology unit, Centre de recherche du CHU de Québec, Laval University, Quebec City, QC, Canada.
3
Institute of Nutrition and Functional Foods (INAF), Laval University, Quebec City, QC, Canada; Endocrinology and Nephrology unit, Centre de recherche du CHU de Québec, Laval University, Quebec City, QC, Canada.
4
Institute of Nutrition and Functional Foods (INAF), Laval University, Quebec City, QC, Canada; School of Nutrition, Laval University, Quebec City, QC, Canada. Electronic address: marie-claude.vohl@fsaa.ulaval.ca.

Abstract

BACKGROUND:

Numbers of single nucleotide polymorphisms (SNPs) associated with fatty acid desaturase activities have been previously identified within the FADS1-FADS2 gene cluster, which encodes delta-5 (D5D) and delta-6 (D6D) desaturases, respectively.

OBJECTIVE:

We aimed at further characterizing the genetic variability associated with D5D and D6D activities on a genome-wide scale.

METHODS:

We conducted a genome-wide association study of D5D and D6D activities in a cohort of 141 individuals from the greater Quebec City metropolitan area using the Illumina HumanOmni5-Quad BeadChip. Estimates of D5D and D6D activities were computed using product-to-precursor fatty acid ratios, arachidonic acid (AA)/dihomo-gamma-linolenic acid (DGLA) for D5D, and DGLA/linoleic acid (LA) for D6D. Levels of fatty acids were measured by gas chromatography in plasma phospholipids.

RESULTS:

We identified 24 previously reported SNPs associated with fatty acid levels and desaturase activities as significantly associated with D5D activity within the FADS1-FADS2 gene cluster (lead SNP rs174566/A>G). Furthermore, we identified 5 novel loci potentially associated with D5D activity at chromosomes 1, 6, 4, 8 and 19. A novel SNP associated with D6D activity and mapped to the ARHGEF10 locus (rs2280885/A>G) was identified, with carriers of the rare allele showing a significant increase in D6D activity and plasma triglyceride levels. After multiple testing correction by permutation, only rs174566 and rs2280885 remained significantly associated to D5D and D6D activity estimates, respectively.

CONCLUSIONS:

These results confirm previous genetic associations within the FADS1-FADS2 gene cluster with D5D activity. A novel genetic variation associated with higher D6D activity within the ARHGEF10 gene is potentially altering plasma triglyceride levels.

KEYWORDS:

ARHGEF10; Fatty acid desaturases; Genome-wide association study; Polyunsaturated fatty acids; Triglycerides

PMID:
29246731
DOI:
10.1016/j.jacl.2017.10.020

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