CHRNA4 and tobacco dependence - From gene regulation to treatment outcome

Context: Given the probable importance of the alpha 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.