title: Phenome-wide Association Study Relating Pretreatment Laboratory Parameters With Human Genetic Variants in AIDS Clinical Trials Group Protocols.
abstract: Background.  Phenome-Wide Association Studies (PheWAS) identify genetic associations across multiple phenotypes. Clinical trials offer opportunities for PheWAS to identify pharmacogenomic associations. We describe the first PheWAS to use genome-wide genotypic data and to utilize human immunodeficiency virus (HIV) clinical trials data. As proof-of-concept, we focused on baseline laboratory phenotypes from antiretroviral therapy-naive individuals. Methods.  Data from 4 AIDS Clinical Trials Group (ACTG) studies were split into 2 datasets: Dataset I (1181 individuals from protocol A5202) and Dataset II (1366 from protocols A5095, ACTG 384, and A5142). Final analyses involved 2547 individuals and 5 954 294 imputed polymorphisms. We calculated comprehensive associations between these polymorphisms and 27 baseline laboratory phenotypes. Results.  A total of 10 584 (0.17%) polymorphisms had associations with P < .01 in both datasets and with the same direction of association. Twenty polymorphisms replicated associations with identical or related phenotypes reported in the Catalog of Published Genome-Wide Association Studies, including several not previously reported in HIV-positive cohorts. We also identified several possibly novel associations. Conclusions.  These analyses define PheWAS properties and principles with baseline laboratory data from HIV clinical trials. This approach may be useful for evaluating on-treatment HIV clinical trials data for associations with various clinical phenotypes.
authors.affiliation: Vanderbilt University School of Medicine , Nashville, Tennessee ; The Center for Systems Genomics , The Pennsylvania State University, University Park.
authors.forename: Carrie B
authors.initials: CB
authors.lastname: Moore
authors.affiliation: The Center for Systems Genomics , The Pennsylvania State University, University Park.
authors.forename: Anurag
authors.initials: A
authors.lastname: Verma
authors.affiliation: The Center for Systems Genomics , The Pennsylvania State University, University Park.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pendergrass
authors.affiliation: The Center for Systems Genomics , The Pennsylvania State University, University Park.
authors.forename: Shefali S
authors.initials: SS
authors.lastname: Verma
authors.affiliation: Vanderbilt University School of Medicine , Nashville, Tennessee.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Johnson
authors.affiliation: Los Angeles Biomed Research Institute at Harbor-UCLA Medical Center , Torrance, California.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
authors.affiliation: Weill Cornell Medical College , New York, New York.
authors.forename: Roy M
authors.initials: RM
authors.lastname: Gulick
authors.affiliation: University of California San Diego.
authors.forename: Richard
authors.initials: R
authors.lastname: Haubrich
authors.affiliation: Harvard University , Boston, Massachusetts.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Robbins
authors.affiliation: The Center for Systems Genomics , The Pennsylvania State University, University Park.
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.affiliation: Vanderbilt University School of Medicine , Nashville, Tennessee.
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
keywords: HIV-1; PheWAS; antiretroviral therapy; clinical trials; pharmacogenomics