Null Results in Brief Lack of Association of 5-HTTLPR Genotype with Smoking Cessation in a Nicotine Replacement Therapy Randomized Trial Marcus R. Munafo `, 1 Elaine C. Johnstone, 2 E. Paul Wileyto, 3 Peter G. Shields, 4 Katherine M. Elliot, 2 and Caryn Lerman 3 1 Department of Experimental Psychology, University of Bristol, Bristol, United Kingdom; 2 Cancer Research UK GPRG, Department of Clinical Pharmacology, University of Oxford, Oxford, United Kingdom; 3 Tobacco Use Research Center, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania; and 4 Lombardi Cancer Center, Georgetown University Medical Center, Washington, District of Columbia Introduction Cigarette 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 pharmacoge- netic 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 trans- porter expression and serotonin uptake (8), while a recent positron emission tomography study also showed an associ- ation 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 posses- sion 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 associa- tion 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 Methods Three 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 and Georgetown University Institutional Review Boards approved all study procedures, and all participants provided written, informed consent. All participants provided samples of whole blood for subsequent genotyping and cotinine analysis. To assess smoking status, telephone interviews were conducted at the end of treatment and at 6-month follow-up. Participants who reported com- pleted abstinence for the previous 7 days were required to complete an in-person visit for biochemical verification of abstinence. Participants were genotyped for the 5-HTTLPR using primers as described by Heils et al. (8). The study is described in detail elsewhere (7). Sustained abstinence, at end of treatment and 6-month follow-up, was the primary outcome measure. Self-reported abstinence at end of treatment and 6-month follow-up was confirmed by exhaled carbon monoxide monitoring (<10 ppm). Participants lost to follow-up were assumed to have relapsed to smoking (12) and coded as such in outcome analyses (i.e., intent to treat analyses). Separate models of outcome at end of treatment and 6-month follow-up were generated within a logistic regression framework because pharmacotherapy was available only during the treatment phase. Age, sex, and nicotine dependence score were entered in the first step, treatment group (transdermal patch and nasal spray) in the second step, and 5-HTTLPR genotype (LL, SL, and SS) and a genotype  treatment group interaction term in 398 Cancer Epidemiol Biomarkers Prev 2006;15(2). February 2006 Cancer Epidemiol Biomarkers Prev 2006;15(2):398 – 400 Received 8/23/05; revised 11/18/05; accepted 12/22/05. Grant support: Transdisciplinary Tobacco Use Research Center grant P5084718 from the National Cancer Institute and the National Institute on Drug Abuse (C. Lerman), Cancer Research UK Programme (E.C. Johnstone), and Unio Internationale Contra Cancrum American Cancer Society International Fellowship for Beginning Investigators (M.R. Munafo `). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Marcus R. Munafo ` , Department of Experimental Psychology, University of Bristol, 8 Woodland Road, Bristol BS8 1TN, United Kingdom. Phone: 44-117-9546841; Fax: 44-117-9288588. E-mail: marcus.munafo@bristol.ac.uk Copyright D 2006 American Association for Cancer Research. doi:10.1158/1055-9965.EPI-05-0648 Downloaded from http://aacrjournals.org/cebp/article-pdf/15/2/398/2264126/398.pdf by guest on 17 June 2022