Multiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202

Pharmacogenet Genomics. 2017 Mar;27(3):101-111. doi: 10.1097/FPC.0000000000000263.

Abstract

Background: 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.

Participants and methods: 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.

Results: 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.

Conclusion: 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy*
  • Acquired Immunodeficiency Syndrome / genetics
  • Adult
  • Anti-Retroviral Agents / administration & dosage*
  • Anti-Retroviral Agents / pharmacokinetics
  • Apolipoprotein A-V / genetics*
  • Apolipoproteins E / genetics*
  • CD4-Positive T-Lymphocytes / cytology
  • Cytochrome P-450 CYP2B6 / genetics*
  • Female
  • Humans
  • Lymphocyte Count
  • Male
  • Middle Aged
  • Pharmacogenomic Variants
  • Phenotype
  • Pilot Projects
  • Polymorphism, Single Nucleotide*
  • Prospective Studies

Substances

  • APOA5 protein, human
  • Anti-Retroviral Agents
  • ApoE protein, human
  • Apolipoprotein A-V
  • Apolipoproteins E
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6

Grant support