We investigated the association of the OPRM1 genotype with long-term smoking cessation and change in body mass index (BMI) following a smoking cessation attempt among smokers who attempted to quit using the nicotine replacement therapy (NRT) patch or placebo in a randomized controlled trial, and were followed-up over an 8-year period following their initial cessation attempt. We also investigated possible sex differences in these relationships, given evidence for sex differences in smoking cessation and central opioid mechanisms, as well as some evidence for sex differences in response to NRT. Our results indicate that OPRM1 genotype may moderate the effect of transdermal nicotine patch compared to placebo during active treatment, with a benefit of active NRT treatment evident in the OPRM1 AA genotype group only and those carrying one or more copies of the G allele demonstrating no benefit of active NRT versus placebo patch. Our results also indicate a sex difference in change in BMI at 8-year follow-up following a smoking cessation attempt, with ex-smokers demonstrating an increase in BMI, and this increase being greater in female subjects than in male subjects. We did not observe any association of OPRM1 genotype with change in BMI, although there was a trend for genotype to influence the observed sex difference in change in BMI over time. Future studies should attempt to replicate these findings, and investigate the relationship between both short-and long-term weight gain and smoking cessation and investigate possible mechanisms that may underlie these processes. Future studies should also investigate the role of OPRM1 genotype and smoking cessation on other appetitive and reward behaviours such as alcohol consumption.

IntroductionCigarette smoking is the leading preventable cause of death worldwide, accounting for at least 30% of all cancer deaths and over three quarters (87%) of lung cancer deaths in developed countries; however, despite progress made in the treatment of tobacco dependence, available Food and Drug Administration -approved treatments are effective for only a fraction of smokers. The wide individual variation in therapeutic response has prompted a growing interest in the study of the role of inherited factors in the efficacy of alternate pharmacotherapies (1). To date, two pharmacogenetic trials of NRT have been conducted. Based on the neurobiology of reward (2, 3), pharmacogenetic analyses have focused on genes in the dopamine pathway (4-6) and the opioid pathway (7).Other promising candidate genes for studies of smoking cessation pharmacogenetics exist. A functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene has been identified (5-HTTLPR) and is known to be associated with altered serotonin activity, with the short (S) form of this polymorphism being associated with reduced transcriptional efficiency of the 5-HTT promoter compared with the long (L) form, thereby decreasing serotonin transporter expression and serotonin uptake (8), while a recent positron emission tomography study also showed an association of this polymorphism with 5-HT1A binding in healthy volunteers (9).A recent meta-analysis of case-control genetic association studies of smoking behaviors (10) noted that the 5-HTT gene showed evidence of association with smoking cessation, in a comparison of current smokers with ex-smokers, with possession of one or more copies of the S allele associated with a reduced likelihood of cessation. It is possible that the S allele influences smoking cessation via increased anxiety-related withdrawal symptomatology, given evidence for an association of this polymorphism with anxiety-related traits (11).However, no study has yet investigated the association of 5-HTTLPR genotype with smoking cessation in an explicitly designed study of smoking cessation or investigated possible genotype  treatment interaction effects.We predicted that possession of one or more copies of the S allele of the 5-HTTLPR polymorphism would be associated with reduced likelihood of successful cessation. We also explored the possibility that NRT delivered via nasal spray might be more effective than NRT delivered via transdermal patch in smokers with one or more copies of the S allele, given that ad lib nasal spray delivery might be better suited to the relief of acute anxiety-related withdrawal symptomatology. Materials and MethodsThree hundred and ninety-seven smokers of European ancestry, recruited by advertisements in local media in Philadelphia and Washington DC from February 2000 to April 2003, participated in this study. The trial was an open-label randomized clinical trial of transdermal patch versus nasal spray nicotine replacement therapy for smoking cessation. The University of Pennsylvania a...

We investigated the association of catechol O-methyltransferase (COMT) genotype with abstinence following a smoking cessation attempt among a large cohort of smokers who attempted to quit using either the nicotine transdermal patch or placebo and were followed up over an 8-year period following their initial cessation attempt. In addition, we examined the possible moderating influence of sex on any association. The genotype  treatment interaction effect at 12-week follow-up indicated a greater benefit of active nicotine replacement treatment compared with placebo on likelihood of abstinence in the COMT Met