Smoking cessation pharmacogenetics: analysis of varenicline and bupropion in
placebo-controlled clinical trials.
Author(s): King DP, Paciga S, Pickering E, Benowitz NL, Bierut LJ, Conti DV, Kaprio J,
Lerman C, Park PW.
Affiliation(s): Pfizer Global Research and Development, Groton, CT 06340, USA.
davidpendletonking@gmail.com
Publication date & source: 2012, Neuropsychopharmacology. , 37(3):641-50
Despite effective therapies for smoking cessation, most smokers find quitting
difficult and most successful quitters relapse. Considerable evidence supports a
genetic risk for nicotine dependence; however, less is known about the
pharmacogenetics of smoking cessation. In the first pharmacogenetic investigation
of the efficacy of varenicline and bupropion, we examined whether genes important
in the pharmacodynamics and pharmacokinetics of these drugs and nicotine predict
medication efficacy and adverse events. Subjects participated in randomized,
double-blind, placebo-controlled smoking cessation clinical trials, comparing
varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, with
bupropion, a norepinephrine/dopamine reuptake inhibitor, and placebo. Primary
analysis included 1175 smokers of European ancestry, and 785 single nucleotide
polymorphisms from 24 genes, representing 254 linkage disequilibrium (LD) bins
(genes included nAChR subunits, additional varenicline-specific genes, and genes
involved in nicotine or bupropion metabolism). For varenicline, continuous
abstinence (weeks 9-12) was associated with multiple nAChR subunit genes
(including CHRNB2, CHRNA5, and CHRNA4) (OR=1.76; 95% CI: 1.23-2.52) (p<0.005);
for bupropion, abstinence was associated with CYP2B6 (OR=1.78; 95% CI: 1.27-2.50)
(p<0.001). Incidence of nausea was associated with several nAChR subunit genes
(OR=0.50; 95% CI: 0.36-0.70) (p<0.0001) and time to relapse after quitting was
associated with HTR3B (HR=1.97; 95% CI: 1.45-2.68) (p<0.0001). These data provide
evidence for multiple genetic loci contributing to smoking cessation and
therapeutic response. Different loci are associated with varenicline vs bupropion
response, suggesting that additional research may identify clinically useful
markers to guide treatment decisions.
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