title: 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.
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. saslibek@uab.edu
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Alexis C
authors.initials: AC
authors.lastname: Frazier-Wood
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yan
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.forename: Eric
authors.initials: E
authors.lastname: Kim
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Tiwari
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Straka
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Tsai
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Korenman
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004843:Epistasis, Genetic; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy* / Q000235:genetics*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D008055:Lipids / Q000097:blood*; D008297:Male; D015201:Meta-Analysis as Topic; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D017063:Outcome Assessment, Health Care / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D014280:Triglycerides / Q000097:blood
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D008055:Lipids; D008869:Microtubule-Associated Proteins; D014280:Triglycerides; C109878:cytoplasmic linker protein 115; D002784:Cholesterol; D011345:Fenofibrate