CHRNA4 and tobacco dependence: from gene regulation to treatment outcome

Context Given the probable importance of the α4 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.