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

Pharmacogenetics and Genomics
David W HaasMarylyn D Ritchie

Abstract

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. 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. 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 t...Continue Reading

References

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Nov 29, 2017·Clinical Drug Investigation·Elke WynbergCaroline Foster

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Citations

Jun 12, 2019·PloS One·Juan ZhaoZhicheng Lin
Aug 24, 2020·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Michael A LeonardDavid W Haas

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Methods Mentioned

BETA
genotyping

Clinical Trials Mentioned

NCT00000919
NCT00013520
NCT00050895
NCT00118898

Software Mentioned

PLINK
EIGENSOFT
ShapeIt2
PrediXcan
liftOver
R

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