Human Molecular Genetics Advance Access originally published online on July 1, 2008
Human Molecular Genetics 2008 17(18):2834-2848; doi:10.1093/hmg/ddn181
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Nicotinic acetylcholine receptor β2 subunit gene implicated in a systems-based candidate gene study of smoking cessation
1 Department of Preventive Medicine, Keck School of Medicine, Zilkha Neurogenetics Institute, University of Southern California, 1501 San Pablo Street, ZNI 445, Los Angeles, CA 90089, USA 2 Evolutionary Systems Biology, Artificial Intelligence Center 3 Center for Health Sciences, SRI International, Menlo Park, CA USA 4 Centre for Addiction and Mental Health and Department of Pharmacology, University of Toronto, Toronto, ON, Canada 5 Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, San Francisco General Hospital Medical Center, Department of Medicine, University of California, San Francisco, CA, USA 6 Departments of Psychiatry and Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed. Tel: +1 3234423140; Fax: +1 3234422448; Email: dconti{at}usc.edu
Received May 13, 2008; Accepted June 17, 2008
Although the efficacy of pharmacotherapy for tobacco dependence has been previously demonstrated, there is substantial variability among individuals in treatment response. We performed a systems-based candidate gene study of 1295 single nucleotide polymorphisms (SNPs) in 58 genes within the neuronal nicotinic receptor and dopamine systems to investigate their role in smoking cessation in a bupropion placebo-controlled randomized clinical trial. Putative functional variants were supplemented with tagSNPs within each gene. We used global tests of main effects and treatment interactions, adjusting the P-values for multiple correlated tests. An SNP (rs2072661) in the 3' UTR region of the β2 nicotinic acetylcholine receptor subunit (CHRNB2) has an impact on abstinence rates at the end of treatment (adjusted P = 0.01) and after a 6-month follow-up period (adjusted P = 0.0002). This latter P-value is also significant with adjustment for the number of genes tested. Independent of treatment at 6-month follow-up, individuals carrying the minor allele have substantially decreased the odds of quitting (OR = 0.31; 95% CI 0.18–0.55). Effect of estimates indicate that the treatment is more effective for individuals with the wild-type (OR = 2.14, 95% CI 1.20–3.81) compared with individuals carrying the minor allele (OR = 0.83, 95% CI 0.32–2.19), although this difference is only suggestive (P = 0.10). Furthermore, this SNP demonstrated a role in the time to relapse (P = 0.0002) and an impact on withdrawal symptoms at target quit date (TQD) (P = 0.0009). Overall, while our results indicate strong evidence for CHRNB2 in ability to quit smoking, these results require replication in an independent sample.
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