Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6)

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.

Keywords: Metabolism; nicotine; pharmacogenetics; smoking cessation.

Figure 1

Pharmacotherapy reduces relapse in fast nicotine metabolizers, but not in slow metabolizers defined by CYP2A6 genotype ^{a a} Time to relapse over 90 days There is a significant interaction between medication and CYP2A6 (interaction effect size=2.81, 95%CI=1.32-5.99, p=0.0075)

Figure 2

Effect of nicotine replacement therapy (NRT) on smoking relapse differs in fast vs. slow nicotine metabolizers defined by CYP2A6 genotype ^a There is a significant interaction between NRT and CYP2A6 (interaction effect size=1.82, 95%CI=1.07-3.10, p=0.028). NRT: Nicotine Replacement Therapy ^a Time to relapse over 90 days. ^b The group with NRT includes all treatment arms with NRT (the NRT arms and the arm receiving both NRT and bupropion. ^c The group without NRT includes all treatment arms without NRT (the placebo arm and the arm receiving bupropion alone).

Figure 3

Trajectory of post-quit smoking quantity varies by treatment and CYP2A6: Fast metabolizers on placebo treatment have a significantly faster escalation into heavy smoking over time (nicotine replacement therapy (NRT) vs. placebo) (3A) A significant interaction between active medication and CYP2A6 on the smoking rate escalation (t=3.13, df=1, p=0.0020). (3B) A trend interaction between NRT combination and CYP2A6 on smoking quantity over time (F=3.75, df =1; p=0.053)

Figure 4

Nicotine replacement therapy (NRT) vs. placebo effect on smoking abstinencea varies with the combined genetic effects of CYP2A6 and CHRNA5 There is a significant interaction between pharmacotherapy (NRT vs. Placebo) and 4 genetic groups (wald=7.44, df=1, p=0.0064). Blue vertical lines are 95% confidence intervals. ^a Continued Abstinence for 3 months. ^b Low vs. risk for CYP2A6 indicates risk for smoking relapse defined by slow vs. fast metabolism. ^c Low vs. risk for CHRNA5 indicates risk for smoking relapse defined by CHRNA5 (rs16969968, rs680244) (low-risk diplotypes: GG_CC, GG_CT, GA_CC and high-risk diplotypes: GG_TT, GA_CT, AA_ CC).