title: Genetic variation in dopaminergic pathways and short-term effectiveness of the nicotine patch.
abstract: Polymorphisms in the dopamine D2 receptor (DRD2 C/T and DRD2 A/G) and in dopamine beta hydroxylase (DBH A/G) have been implicated in modulation of smoking and other reward-seeking behaviours. We hypothesized that these alleles would predict the outcome of nicotine patch therapy for smoking cessation. In 1991-93, we performed a randomized controlled trial of the nicotine patch on 1686 heavy smokers (> or = 15 cigarettes/day). In 1999-2000, we contacted 1532 of the 1612 subjects still available; 767 (50%) completed a questionnaire and gave a blood sample. In the 755 cases in which DNA was successfully genotyped, we examined associations between the polymorphisms in DRD2 and DBH, and smoking cessation. At 1 week, the patch was more effective for smokers with DRD2 CT/TT genotype [patch/placebo odds ratio (OR) 2.8, 95% confidence interval (CI) 1.7-4.6] than with CC (OR 1.4, 0.9-2.1; P for difference in ORs 0.04). Smokers with both DRD2 CT/TT and DBH GA/AA genotypes had an OR of 3.6 (2.0-6.5) compared to 1.4 (1.0-2.1) for others (P = 0.01). At 12 weeks, the ORs for these genotypic groups were 3.6 (1.7-7.8) and 1.4 (0.9-2.3), respectively (P = 0.04). There was no association between patch effectiveness and DRD2 exon 8. Short-term effectiveness of the nicotine patch may be related to dopamine beta-hydroxylase and dopamine D2 receptor genotype. Our results support the need for further investigation into personalized therapies for smoking cessation based on individual genotype.
authors.affiliation: Cancer Research UK General Practice Research Group, Department of Clinical Pharmacology, University of Oxford, Oxford, UK. elaine.johnstone@clinpharm.ox.ac.uk
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Johnstone
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Yudkin
authors.forename: Kate
authors.initials: K
authors.lastname: Hey
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Roberts
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Welch
authors.forename: Michael F
authors.initials: MF
authors.lastname: Murphy
authors.forename: Siân E
authors.initials: SE
authors.lastname: Griffiths
authors.forename: Robert T
authors.initials: RT
authors.lastname: Walton
mesh_terms: D000328:Adult; D000368:Aged; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000008:administration & dosage* / Q000009:adverse effects; D016017:Odds Ratio; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D015398:Signal Transduction; D016540:Smoking Cessation / Q000379:methods*
chemical_list: D017448:Receptors, Dopamine D2; D009538:Nicotine; D004299:Dopamine beta-Hydroxylase