Variants Identified in a GWAS Meta-Analysis for Blood Lipids Are Associated with the Lipid Response to Fenofibrate

Abstract

A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value≤0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n = 267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. Finally, we present strong evidence for epistasis (P-value for interaction = 0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.

The N-Reductive System Composed of Mitochondrial Amidoxime Reducing Component (mARC), Cytochrome b5 (CYB5B) and Cytochrome b5 Reductase (CYB5R) Is Regulated by Fasting and High Fat Diet in Mice

“…The fact that the mARC proteins and its electron transfer partners decrease with fasting and that mARC2 and the protein assumed to be mARC1 increases with HFD but not with obese ob/ob-mice, reveals that the proteins are connected with food intake and energy supply. Other recent studies support this conclusion: A single nucleotide polymorphism (SNP) with the mARC1 locus was shown to associate with changes in plasma concentration of both total cholesterol and low density lipoprotein cholesterol [27] and others found an influence of this SNP on both baseline low density lipoproteins and the response to fenofibrate [28]. Neve and coworkers [4] proved an involvement of the mARC2 protein in lipid synthesis in 3T3-adipocytes.…”

Functional Variants of Lipid Level Modifier MLXIPL, GCKR, GALNT2, CILP2, ANGPTL3 and TRIB1 Genes in Healthy Roma and Hungarian Populations

“…metabolic consequences, including triglyceride level increases, confirming risk for cardiovascular diseases, metabolic syndrome or for cerebrovascular diseases, especially stroke events [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The National Cholesterol Education Program (NCEP) in 2001 ascertained several markers which are in strong association with coronary risk, stratified as risk factors related to lifestyle, such as physical inactivity, obesity, atherogenic diet; and emerging risk factors, as lipoprotein profile, homocysteine level, changed fasting glycaemia and evidence of subclinical atherosclerosis.…”

“…Several of them are associated with elevated triglyceride levels and higher risks for ischemic stroke and cardio-or cerebrovascular diseases or for metabolic syndrome [4, 5, 8-11, 21, 22]. Recently, other triglyceride modifying polymorphisms came into focus, which may also have role in development of different diseases [2,12,15,16,19,[23][24][25]. Some variants of these are mentioned in connection with increased, while others with decreased triglyceride levels [16,23,24,26,27].…”

The Involvement of Mitochondrial Amidoxime Reducing Components 1 and 2 and Mitochondrial Cytochrome b5 in N-Reductive Metabolism in Human Cells

“…Furthermore, mARC2 expression has been found to be up-regulated in diabetic kidneys and by glucose in renal cells (10). Moreover, an association of mARC1 with lipid metabolism was recently postulated (11)(12)(13).…”