Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion.

AIMS To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies. DESIGN Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support. SETTING Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2). PARTICIPANTS A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year. MEASUREMENTS Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4 VNTR], SLC6A3,3' VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment. FINDINGS Significant associations of the AGES (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, P = 0.009) and of the DRD4 VNTR (HR = 1.29, 95% CI = 1.17-1.41, P = 0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error = -0.18 [0.07], P = 0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo. CONCLUSIONS A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.