title: Multiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202.
abstract: High-throughput approaches are increasingly being used to identify genetic associations across multiple phenotypes simultaneously. Here, we describe a pilot analysis that considered multiple on-treatment laboratory phenotypes from antiretroviral therapy-naive patients who were randomized to initiate antiretroviral regimens in a prospective clinical trial, AIDS Clinical Trials Group protocol A5202.
  
  
  
  From among 5 9545 294 polymorphisms imputed genome-wide, we analyzed 2544, including 2124 annotated in the PharmGKB, and 420 previously associated with traits in the GWAS Catalog. We derived 774 phenotypes on the basis of context from six variables: plasma atazanavir (ATV) pharmacokinetics, plasma efavirenz (EFV) pharmacokinetics, change in the CD4+ T-cell count, HIV-1 RNA suppression, fasting low-density lipoprotein-cholesterol, and fasting triglycerides. Permutation testing assessed the likelihood of associations being by chance alone. Pleiotropy was assessed for polymorphisms with the lowest P-values.
  
  
  
  This analysis included 1181 patients. At P less than 1.5×10, most associations were not by chance alone. Polymorphisms with the lowest P-values for EFV pharmacokinetics (CYPB26 rs3745274), low-density lipoprotein -cholesterol (APOE rs7412), and triglyceride (APOA5 rs651821) phenotypes had been associated previously with those traits in previous studies. The association between triglycerides and rs651821 was present with ATV-containing regimens, but not with EFV-containing regimens. Polymorphisms with the lowest P-values for ATV pharmacokinetics, CD4 T-cell count, and HIV-1 RNA phenotypes had not been reported previously to be associated with that trait.
  
  
  
  Using data from a prospective HIV clinical trial, we identified expected genetic associations, potentially novel associations, and at least one context-dependent association. This study supports high-throughput strategies that simultaneously explore multiple phenotypes from clinical trials' datasets for genetic associations.
authors.affiliation: aThe Center for Systems Genomics, The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park bBiomedical and Translational Informatics, Geisinger Health System, Danville, Pennsylvania cLos Angeles Biomedical Research Institute at Harbor, UCLA Medical Center, Torrance, California dUniversity of Rochester Medical Center, Rochester eDepartment of Pharmacy Practice, Center for Integrated Global Biomedical Sciences, University at Buffalo, SUNY, Buffalo, New York fVanderbilt University School of Medicine gMeharry Medical College, Nashville, Tennessee, USA.
authors.forename: Anurag
authors.initials: A
authors.lastname: Verma
authors.forename: Yuki
authors.initials: Y
authors.lastname: Bradford
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Pendergrass
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
authors.forename: Charles
authors.initials: C
authors.lastname: Venuto
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000072040:Apolipoprotein A-V / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D006801:Humans; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: C437704:APOA5 protein, human; D044966:Anti-Retroviral Agents; C000612345:ApoE protein, human; D000072040:Apolipoprotein A-V; D001057:Apolipoproteins E; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6