Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene ( CYP2A6 )
Year: 2013
Type: article
Abstract: BACKGROUND AND AIMS: Evidence suggests that both the nicotinic receptor α5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes. DESIGN: Placebo-controlled randomized smoking cessation trial. SETTING: Ambulatory care facility in Wisconsin, USA. PARTICIPANTS: Smokers (n = 709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy. MEASUREMENTS: Survival analysis was used to model time to relapse using nicotine metabolism derived from CYP2A6 genotype-based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function. FINDINGS: CYP2A6-defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days [hazard ratio (HR) = 2.81, 95% confidence interval (CI) = 1.32-5.99, P = 0.0075], with pharmacotherapy significantly slowing relapse in fast (HR = 0.39, 95% CI = 0.28-0.55, P = 1.97 × 10(-8)), but not slow metabolizers (HR = 1.09, 95% CI = 0.55-2.17, P = 0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with CYP2A6-defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from CYP2A6 and CHRNA5 (Wald = 7.44, d.f. = 1, P = 0.0064). CONCLUSIONS: Nicotine replacement therapy is effective among individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions.
Source: Addiction
DOI: 10.1111/add.12353
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Wellcome Trust, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G132635143, G1756984421, G1867228831, G2196166416, G2196283476, G2202404319, G2252333647, G2520485102, Training in Translational Tobacco Science, Study of Addiction: Genetics and Environment, G2775335414, Washington University Institute of Clinical and Translational Sciences, G370871742, G3799582765, G407586344, Genome Wide Association Coordinating Center, HUMAN GENETIC VARIATION IN SMOKING AND ADDICTION RISK, G4738469230, G5485136719, JH/CIDR Genotyping for Genome-Wide Association Studies, Washington University Institute of Clinical and Translational Sciences, Washington University Institute of Clinical and Translational Sciences (KL2), G8267674335, G858805679, G948540326
OpenAlex ID: W1685552966