CONTEXT: Given the probable importance of the alpha4 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.
CONTEXT: Given the probable importance of the alpha4 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.
Authors: Linda M Lucero; Maegan M Weltzin; J Brek Eaton; John F Cooper; Jon M Lindstrom; Ronald J Lukas; Paul Whiteaker Journal: J Biol Chem Date: 2015-12-07 Impact factor: 5.157
Authors: Helen M Kamens; Jill Miyamoto; Matthew S Powers; Kasey Ro; Marissa Soto; Ryan Cox; Jerry A Stitzel; Marissa A Ehringer Journal: Neuropharmacology Date: 2015-08-25 Impact factor: 5.250
Authors: Riju Ray; James Loughead; Ze Wang; John Detre; Edward Yang; Ruben Gur; Caryn Lerman Journal: Behav Brain Res Date: 2008-06-05 Impact factor: 3.332