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

TitleMultiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202.
Publication TypeJournal Article
Year of Publication2017
AuthorsVerma A, Bradford Y, Verma SS, Pendergrass SA, Daar ES, Venuto C, Morse GD, Ritchie MD, Haas DW
JournalPharmacogenet Genomics
Volume27
Issue3
Pagination101-111
Date Published2017 Mar
ISSN1744-6880
KeywordsAcquired Immunodeficiency Syndrome, Adult, Anti-Retroviral Agents, Apolipoprotein A-V, Apolipoproteins E, CD4-Positive T-Lymphocytes, Cytochrome P-450 CYP2B6, Female, Humans, Lymphocyte Count, Male, Middle Aged, Pharmacogenomic Variants, Phenotype, Pilot Projects, Polymorphism, Single Nucleotide, Prospective Studies
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.

DOI10.1097/FPC.0000000000000263
Alternate JournalPharmacogenet. Genomics
PubMed ID28099408
PubMed Central IDPMC5285297
Grant ListU01 AI069502 / AI / NIAID NIH HHS / United States
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