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

Juan de Toro-Martín; Frédéric Guénard; Iwona Rudkowska; Simone Lemieux; Patrick Couture; Marie-Claude Vohl

doi:10.1016/j.jacl.2017.10.020

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

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

Authors

Juan de Toro-Martín¹, Frédéric Guénard¹, Iwona Rudkowska², Simone Lemieux¹, Patrick Couture³, Marie-Claude Vohl⁴

Affiliations

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.

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

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Delta-5 Fatty Acid Desaturase
Female
Gene Expression Profiling
Gene Frequency
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods
Genotype
Humans
Hypertriglyceridemia / enzymology
Hypertriglyceridemia / genetics*
Linoleoyl-CoA Desaturase / genetics*
Linoleoyl-CoA Desaturase / metabolism
Male
Polymorphism, Single Nucleotide*
Rho Guanine Nucleotide Exchange Factors / genetics*
Triglycerides / blood
Young Adult

Substances

ARHGEF10 protein, human
Delta-5 Fatty Acid Desaturase
Rho Guanine Nucleotide Exchange Factors
Triglycerides
FADS1 protein, human
Linoleoyl-CoA Desaturase

Grants and funding

MOP110975/CIHR/Canada