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




Variants Identified in a GWAS Meta-Analysis for Blood Lipids Are Associated with the Lipid Response to Fenofibrate - Download this document for free, or read online. Document in PDF available to download.

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.



Author: Stella Aslibekyan , Mark O. Goodarzi, Alexis C. Frazier-Wood, Xiaofei Yan, Marguerite R. Irvin, Eric Kim, Hemant K. Tiwari, Xiuqi

Source: http://plos.srce.hr/



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