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From Gene Regulation to Treatment Outcome

Kent E. Hutchison, PhD; David L. Allen, PhD; Francesca M. Filbey, PhD; Christopher Jepson, PhD; Caryn Lerman, PhD; Neal L. Benowitz, MD; Jerry Stitzel, PhD; Angela Bryan, PhD; John McGeary, PhD; Heather M. Haughey, PhD

Arch Gen Psychiatry. 2007;64(9):1078-1086.

Context  Given the probable importance of the 4 subunit of the neuronal nicotinic acetylcholine receptor, the gene that codes for this subunit (CHRNA4) represents an excellent starting point for a genetic investigation of smoking behavior.

Objective  To achieve a better understanding of the role of this gene in the cause and treatment of tobacco dependence, we adopted a transdisciplinary pharmacogenetic approach.

Design  Study at the behavioral and clinical levels of analysis.

Setting  Academic research.

Participants  Smokers (n = 316) between the ages of 18 and 50 years were recruited from the Denver, Colorado, metropolitan area.

Main Outcome Measures  Bioinformatics analyses, cell culture experiments, and analyses of CHRNA4 expression and nicotine binding in postmortem human brain tissue advanced 2 single-nucleotide polymorphisms (rs6122429 and rs2236196).

Results  Both single-nucleotide polymorphisms were associated with subjective responses to smoking in the laboratory among 316 smokers. Likewise, among 353 participants in a clinical trial, rs2236196 was associated with smoking cessation outcomes.

Conclusions  Results of analyses ranging from basic biological approaches to clinical outcome data provide consistent evidence that 2 single-nucleotide polymorphisms in CHRNA4 are functional at a biological level and are associated with nicotine dependence phenotypes. This interdisciplinary approach to the genetics of nicotine dependence provides a model for testing how functional genetic variation is translated from changes in messenger RNA and protein to individual differences in behavior and treatment outcome.

Author Affiliations: Departments of Psychology (Drs Hutchison, Filbey, Bryan, and Haughey) and Integrated Physiology (Drs Allen and Stitzel), University of Colorado at Boulder; Department of Psychiatry and Tobacco Use Research Center, University of Pennsylvania, Philadelphia (Drs Jepson and Lerman); Division of Clinical Pharmacology, Department of Medicine, and Department of Biopharmaceutical Sciences, University of California, San Francisco (Dr Benowitz); and Providence Veterans Affairs Medical Center and Center for Alcohol and Addiction Studies, Brown University, Providence, Rhode Island (Dr McGeary).

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