title: A genome-wide study of lipid response to fenofibrate in Caucasians: a combined analysis of the GOLDN and ACCORD studies.
abstract: Fibrates are commonly prescribed for hypertriglyceridemia, but they also lower LDL cholesterol and increase HDL cholesterol. Large interindividual variations in lipid response suggest that some patients may benefit more than others and genetic studies could help identify such patients.
  
  
  
  We carried out the first genome-wide association study of lipid response to fenofibrate using data from two well-characterized clinical trials: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study. Genome-wide association study data from both studies were imputed to the 1000 Genomes CEU reference panel (phase 1). Lipid response was modeled as the log ratio of the post-treatment lipid level to the pretreatment level. Linear mixed models (GOLDN, N=813 from 173 families) and linear regression models (ACCORD, N=781) adjusted for pretreatment lipid level, demographic variables, clinical covariates, and ancestry were used to evaluate the association of genetic markers with lipid response. Among Caucasians, the results were combined using inverse-variance weighted fixed-effects meta-analyses. The main findings from the meta-analyses were examined in other ethnic groups from the HyperTG study (N=267 Hispanics) and ACCORD (N=83 Hispanics, 138 African Americans).
  
  
  
  A known lipid locus harboring the pre-B-cell leukemia homeobox 4 (PBX4) gene on chromosome 19 is important for LDL cholesterol response to fenofibrate (smallest P=1.5×10). The main results replicated with nominal statistical significance in Hispanics from ACCORD (P<0.05).
  
  
  
  Future research should evaluate the usefulness of this locus to refine clinical strategies for lipid-lowering treatments.
authors.affiliation: Departments of aEpidemiology bBiostatistics, University of Alabama at Birmingham, Birmingham, Alabama cDepartment of Statistics, North Carolina State University, Raleigh dUAB Biostatistics, Diabetes Center for Research, University of North Carolina at Chapel Hill School of Medicine eUAB Epidemiology, Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina fDepartment of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota gNCState Biostatistics, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts hDepartment of Genetics, Division of Statistical Genomics, Washington University in St Louis, St Louis, Missouri iLaboratory of Statistical and Mathematical Genetics jLaboratory for Biochemistry, Molecular Phenotyping, and Microarray kInstitute for Translational Genomics and Population Sciences, Harbor-UCLA Medical Center, Torrance, California, USA.
authors.forename: Marguerite R
authors.initials: MR
authors.lastname: Irvin
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Rotroff
authors.forename: Stella
authors.initials: S
authors.lastname: Aslibekyan
authors.forename: Degui
authors.initials: D
authors.lastname: Zhi
authors.forename: Bertha
authors.initials: B
authors.lastname: Hidalgo
authors.forename: Alison
authors.initials: A
authors.lastname: Motsinger-Reif
authors.forename: Skylar
authors.initials: S
authors.lastname: Marvel
authors.forename: Vinodh
authors.initials: V
authors.lastname: Srinivasasainagendra
authors.forename: Steven A
authors.initials: SA
authors.lastname: Claas
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Straka
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Borecki
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Ida Y D
authors.initials: IY
authors.lastname: Chen
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
mesh_terms: D002986:Clinical Trials as Topic; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy* / Q000235:genetics*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics*; D008055:Lipids / Q000097:blood*; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D044465:White People
chemical_list: D005819:Genetic Markers; D000960:Hypolipidemic Agents; D008055:Lipids; D011345:Fenofibrate