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A Common Variant in ARHGEF10 Alters Delta-6 Desaturase Activity and Influence Susceptibility to Hypertriglyceridemia

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A Common Variant in ARHGEF10 Alters Delta-6 Desaturase Activity and Influence Susceptibility to Hypertriglyceridemia A common variant in ARHGEF10 alters delta-6 desaturase activity and influence susceptibility to hypertriglyceridemia Authors: Juan de Toro-Martín1,2, Frédéric Guénard1,2, Iwona Rudkowska3, Simone Lemieux1,2, Patrick Couture1,3 and Marie-Claude Vohl1,2* 1 Institute of Nutrition and Functional Foods (INAF), Laval University, Quebec City, QC, G1V 0A6, Canada. 2 School of Nutrition, Laval University, Quebec City, QC, G1V 0A6, Canada. 3 Endocrinology and Nephrology unit, Centre de recherche du CHU de Québec – Laval University, Quebec City, QC, G1V 4G2, Canada. Running title: A novel D6D-associated SNP in ARHGEF10 * Corresponding author: Marie-Claude Vohl, Ph.D. Institute of Nutrition and Functional Foods (INAF) Laval University 2440 Hochelaga Blvd Quebec, QC Canada, G1V 0A6 [email protected] +1 (418) 656-2131 (4676) 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. Introduction Polyunsaturated fatty acids (PUFA) have been extensively reported as relevant factors involved in maintaining several physiological functions. Among others, relative amounts of omega-3 (n-3) and omega-6 (n-6) PUFA, specially low n-3/n-6 ratios, have been associated with metabolic disorders, such as obesity, metabolic syndrome or inflammation 1–3, as well as with an adequate lipid profile control 4. Although PUFA levels in the organism mainly depends on dietary intake, an alternative and not negligible source of PUFA comes from the conversion of the essential n-3 alpha-linolenic (ALA) and n-6 linoleic (LA) fatty acids 5. The process of de novo synthesis of long-chain PUFA is governed by enzymes belonging to two different classes, called elongases and desaturases, encoded by genes from ELOVL (ELOVL2 and ELOVL5) and FADS families (FADS1 and FADS2), respectively 6. The process of elongation and desaturation ends up giving way to the principal forms of n-3, eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), and n-6 long-chain PUFA, dihomo-gamma-linolenic (DGLA) and arachidonic acid (AA) 7. Specifically, desaturation steps are catalyzed by two enzymes, called delta-6 (D6D) and delta-5 (D5D) desaturases, encoded by FADS1 and FADS2, respectively. Previous studies have revealed that single nucleotide polymorphisms (SNPs) located within or near the FADS1-FADS2 gene cluster on chromosome 11 may alter desaturation rates of both D6D and D5D, as well as the associated endogenous levels of n-3 and n-6 PUFA 8–10. Therefore, the aim of this study was to replicate these findings and to reveal novel loci associated to desaturase activities in the Fatty Acid Sensor (FAS) study population 11. Furthermore, in view of the pronounced inter-individual variability in the plasma triglyceride (TG) response to a n-3 PUFA supplementation 12 and the consistent association between genetic variants altering desaturase activities and plasma lipid levels 13,14, we also analyzed the impact of desaturase-associated SNPs on plasma lipid profile. Methods Study population The cohort used in this work comprised a total of 141 subjects from the FAS study. In this previous study, 254 subjects from the Quebec City metropolitan area were recruited (registered at ClinicalTrials.gov as NCT01343342) in order to identify determinants of the plasma TG response to an n-3 PUFA (EPA and DHA) supplementation. Trial details and participant selection criteria are extensively described in 12. Briefly, participants of the FAS study were metabolically healthy with a BMI between 25 and 40 kg/m 2 and not taking any medication to treat lipid disorders or n-3 PUFA supplements for at least 6 months prior the intervention study. The experimental protocol was approved by the ethics committees of Centre Hospitalier Universitaire de Québec Research Center and Laval University and was conducted in accordance with the Declaration of Helsinki. From the 254 subjects, 210 completed the intervention protocol and were classified as responders (having a reduction in plasma TG levels > 0.01mM) and non-responders (having no reduction in plasma TG levels). From these 210 participants, genotypes of those exhibiting the most extreme TG response after the n-3 PUFA supplementation were selected for the present study. Extreme TG responders were selected according to a threshold based on the technical error of measurement (TEM) 15. Briefly, participants classified as responders and showing changes in plasma TG levels greater than 0.22 mM (1.5 TEM) after the n-3 PUFA supplementation were considered as extreme TG responders (n = 81). Non-responders were always defined as those showing no reduction in plasma TG levels (n = 60). Determination of biochemical parameters and desaturase activities Anthropometric and biochemical parameters – plasma TG, total cholesterol (TC), HDL- cholesterol (HDL-C) and LDL-cholesterol (LDL-C) – of study participants were performed after a two-week run-in period, and before the n-3 PUFA supplementation, and they are described in detail elsewhere 10,16. Fatty acid extraction was performed in blood samples collected after 12h overnight fast prior the n-3 PUFA supplementation. Plasma was separated by centrifugation and frozen for subsequent analyses. Plasma lipids were extracted with chloroform:methanol (2:1, v/v), according to a modified Folch method, as previously described 16. Total phospholipids were separated by thin layer chromatography using a combination of acetic acid and isopropyl ether. Fatty acids of isolated phospholipids were then methylated and capillary gas chromatography was used to obtain n-3 (ALA, EPA and DHA) and n-6 (AL, DGLA and AA) fatty acid profiles. Capillary gas chromatography was performed using a temperature gradient on a HP5890 gas chromatograph (Hewlett Packard, Toronto, Canada) equipped with a HP- 88 capillary column (100m x 0.25 mm inner diameter x 0.20µm film thickness; Agilent Technologies, Palo Alto, CA) coupled with a flame ionization detector. Helium was used as carrier gas (split ratio 1:80). The identification of n-3 and n-6 PUFA was performed according to their retention time, using the following standard mixtures as a basis for comparison: the FAME 37 mix (Supelco Inc., Bellefonte, PA) and the GLC-411 FA mix (NuChek Prep Inc, Elysian, MN), as well as the methylated n-6 docosapentaenoic acid (n-6 DPA; Larodan AB, Malmö, Sweden) and n-3 DPA (Supelco Inc., Bellefonte, PA). Fatty acid levels were finally expressed as a percentage of total fatty acids in plasma phospholipids. Estimates of desaturase activities were calculated as n-6 PUFA product- to-precursor ratios as follows: D5D activity was determined as the ratio AA/DGLA, and D6D activity as the ratio DGLA/LA, as previously described 9. Genotyping Genomic DNA was extracted form whole blood using the GenElute Gel Extraction Kit (Sigma-Aldrich Co., St. Louis, MO) and quantified with an Agilent 2100 Bioanalyser (Agilent Technologies, Palo Alto, CA). Samples were genotyped using the Illumina HumanOmni-5-Quad Bead-Chip (Illumina, San Diego, CA) at the McGill University and Génome Québec Innovation Centre (Montreal, Canada), according to the manufacturer’s instructions. Each HumanOmni-5-Quad BeadChip contained 4,301,331 markers. Sample quality was assessed by signal intensity using R 17 and overall call rate using PLINK 1.9 18. The mean call rate across all samples was 99.84%. None of the 141 samples analyzed were excluded due to low signal intensity or low overall call rate (<90%). Genome-wide association study The genome-wide association study (GWAS) SNP inclusion criteria were a minor allele frequency >1%, a call rate >95%, and a Hardy-Weinberg equilibrium (HWE) P>1×10-7. Allele frequencies and HWE tests were calculated using PLINK 1.9. A total of 1,632,526 SNPs were excluded, leaving 2,668,805 SNPs for statistical analyses. For each SNP, linear associations under an additive model of inheritance were tested in PLINK 1.9 with estimates of D5D and D6D activities used as continuous variables. A potential population structure was corrected by principal component analysis (PCA) and eigenvectors were included as co-variables in the model of linear association. Genomic control inflation factors (λ) were obtained for both association tests to account for false positives. The genomic inflation observed in the association tests for estimates of D5D (λ = 1.26) and D6D (λ = 1.06) activities was corrected, yielding a final genomic control value of 1.09 and 1.03, for D5D and D6D, respectively.
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