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Pharmacogenet Genomics. 2018 Jul;28(7):179-187. doi: 10.1097/FPC.0000000000000341.

Brain neurotransmitter transporter/receptor genomics and efavirenz central nervous system adverse events.

Author information

1
Department of Medicine, Vanderbilt University School of Medicine.
2
Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee.
3
Department of Genetics.
4
Institute for Biomedical Informatics, University of Pennsylvania, Perelman School of Medicine, Philadelphia.
5
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
6
Department of Medicine, Weill Cornell Medicine, New York City.
7
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
8
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
9
David Geffen School of Medicine at UCLA, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute, Los Angeles, California.
10
University at Buffalo, SUNY, Buffalo, New York.
11
University of Alabama at Birmingham, Birmingham, Alabama, USA.

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.

PMID:
29847509
PMCID:
PMC6010221
DOI:
10.1097/FPC.0000000000000341
[Indexed for MEDLINE]
Free PMC Article

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