@article{4b7b29f316884c91819cbfc6f9080a79,
title = "Brain neurotransmitter transporter/receptor genomics and efavirenz central nervous system adverse events",
abstract = "Objective We characterized associations between central nervous system (CNS) adverse events and brain neurotransmitter transporter/receptor genomics among participants randomized to efavirenz-containing regimens in AIDS Clinical Trials Group studies in the USA. Participants and methods Four clinical trials randomly assigned treatment-naive participants to efavirenzcontaining regimens. Genome-wide genotype and PrediXcan were used to infer gene expression levels in tissues including 10 brain regions. Multivariable regression models stratified by race/ethnicity were adjusted for CYP2B6/CYP2A6 genotypes that predict plasma efavirenz exposure, age, and sex. Combined analyses also adjusted for genetic ancestry. Results Analyses included 167 cases with grade 2 or greater efavirenz-consistent CNS adverse events within 48 weeks of study entry, and 653 efavirenz-tolerant controls. CYP2B6/CYP2A6 genotype level was independently associated with CNS adverse events (odds ratio: 1.07; P=0.044). Predicted expression of six genes postulated to mediate efavirenz CNS side effects (SLC6A2, SLC6A3, PGR, HTR2A, HTR2B, HTR6) were not associated with CNS adverse events after correcting for multiple testing, the lowest P value being for PGR in hippocampus (P=0.012), nor were polymorphisms in these genes or AR and HTR2C, the lowest P value being for rs12393326 in HTR2C (P=6.7 × 10-4). As a positive control, baseline plasma bilirubin concentration was associated with predicted liver UGT1A1 expression level (P=1.9 × 10-27). Conclusion Efavirenz-related CNS adverse events were not associated with predicted neurotransmitter transporter/receptor gene expression levels in brain or with polymorphisms in these genes. Variable susceptibility to efavirenz-related CNS adverse events may not be explained by brain neurotransmitter transporter/receptor genomics.",
author = "Haas, {David W.} and Yuki Bradford and Anurag Verma and Verma, {Shefali S.} and Eron, {Joseph J.} and Gulick, {Roy M.} and Riddler, {Sharon A.} and Sax, {Paul E.} and Daar, {Eric S.} and Morse, {Gene D.} and Acosta, {Edward P.} and Ritchie, {Marylyn D.}",
note = "Funding Information: Joseph J. Eron has received research support from grants awarded to UNC from BMS, AbbVie, Janssen, ViiV Healthcare, and Gilead. He is a consultant to BMS, AbbVie, Janssen, ViiV Healthcare, Merck, and Gilead. Paul E. Sax has received research support from grants awarded to Brigham and Women{\textquoteright}s Hospital from BMS, ViiV, and Gilead. He is a consultant to BMS, AbbVie, Janssen, ViiV, Merck, and Gilead. Eric S. Daar has received research support from grants awarded to Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center from Gilead, Merck and ViiV. He is a consultant for Bristol-Myers Squibb, Janssen, Merck, Teva, and ViiV. Sharon A. Riddler has received research support from grants awarded to University of Pittsburgh from Gilead Sciences and Bristol-Myers Squibb. For the remaining authors, there are no conflicts of interest. Funding Information: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636, and UM1 AI106701. This work was supported by the AIDS Clinical Trials Group funded by the National Institute of Allergy and Infectious Diseases (AI068636, AI038858, AI068634, AI038855). Grant support included AI069439, TR000445 (DWH), AI077505 (DWH), and AI50410 (University of North Carolina at Chapel Hill Center for AIDS Research). Clinical Research Sites that participated in ACTG protocols ACTG384, A5095, A5142, and A5202, and collected DNA under protocol A5128, were supported by the following grants from NIAID: AI069477, AI027675, AI073961, AI069474, AI069432, AI069513, AI069423, AI050410, AI069452, AI69450, AI054907, AI069428, AI045008, AI069495, AI069415, AI069556, AI069484, AI069424, AI069532, AI069419, AI069471, AI025859, AI069418, AI050409, AI069501, AI069502, AI069511, AI069434, AI069465, AI069494, AI069472, AI069470, AI046376, AI072626, AI027661, AI034853, AI069447, AI032782, AI027658, AI27666, AI058740, AI046370, and by the following grants from the National Center for Research Resources (NCRR): RR00051, RR00046, RR025747, RR025777, RR024160, Publisher Copyright: Copyright {\textcopyright} 2018 Wolters Kluwer Health, Inc. All rights reserved.",
year = "2018",
doi = "10.1097/FPC.0000000000000341",
language = "English (US)",
volume = "28",
pages = "179--187",
journal = "Pharmacogenetics and Genomics",
issn = "1744-6872",
publisher = "Lippincott Williams and Wilkins",
number = "7",
}