Brain neurotransmitter transporter/receptor genomics and efavirenz central nervous system adverse events. Issue 7 (July 2018)

• Record Type: Journal Article
• Authors: Haas, David W.; Bradford, Yuki; Verma, Anurag; Verma, Shefali S.; Eron, Joseph J.; Gulick, Roy M.; Riddler, Sharon A.; Sax, Paul E.; Daar, Eric S.; Morse, Gene D.; Acosta, Edward P.; Ritchie, Marylyn D.
• Is Part Of: Pharmaocogenetics and genomics. Volume 28:Issue 7(2018)
• Publication Date: 2018-07
• Subjects: efavirenz -- HIV -- neurotransmitter receptor -- neurotransmitter transporter -- pharmacogenomics; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000341
• Languages: English
• ISSNs: 1744-6872

Abstract

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 efavirenz-containing 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. Abstract : Supplemental Digital Content is available in the text.