Multiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202. Issue 3 (March 2017)

• Record Type: Journal Article
• Authors: Verma, Anurag; Bradford, Yuki; Verma, Shefali S.; Pendergrass, Sarah A.; Daar, Eric S.; Venuto, Charles; Morse, Gene D.; Ritchie, Marylyn D.; Haas, David W.
• Is Part Of: Pharmaocogenetics and genomics. Volume 27:Issue 3(2017:Mar.)
• Publication Date: 2017-03
• Subjects: antiretroviral therapy -- clinical trials -- HIV-1 -- pharmacogenomics -- phenome-wide association studies; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000263
• Languages: English
• ISSNs: 1744-6872

Abstract

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 −4, 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. Abstract : Supplemental Digital Content is available in the text.