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Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample.

ABSTRACT: Neuronal nicotinic acetylcholine receptors are activated by both endogenous acetylcholine and exogenous nicotine, making sequence variations in these receptors likely candidates for association with tobacco phenotypes. Previous studies have found evidence for significant association between single nucleotide polymorphisms (SNPs) in the genomic region containing the CHRNA6 and CHRNB3 genes and tobacco behaviors. In this study, we provide support for an association between these genes and tobacco dependence in the National Youth Survey Family Study wave 10, a nationally representative sample of households. Eight SNPs in the CHRNA6 and CHRNB3 genomic region were genotyped in 1051 subjects, approximately half of whom are members of sibling pairs. Genetic association with DSM-IV dependence was assessed using a family-based approach as implemented in the statistical package PBAT. Individual SNPs were tested for association with quit attempts and overall dependence. Variation in CHRNA6 was found to be associated with tobacco dependence (p=0.007 in Caucasians). SNPs in CHRNB3 were found to be associated with the number of quit attempts (p=0.0024). Together these results further implicate the region downstream of CHRNA6 and the region upstream of CHRNB3 in risk of nicotine dependence.

SUBMITTER: Hoft NR

PROVIDER: S-EPMC2915837 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample.

Hoft Nicole R NR Corley Robin P RP McQueen Matthew B MB Schlaepfer Isabel R IR Huizinga David D Ehringer Marissa A MA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20080813 3

Neuronal nicotinic acetylcholine receptors are activated by both endogenous acetylcholine and exogenous nicotine, making sequence variations in these receptors likely candidates for association with tobacco phenotypes. Previous studies have found evidence for significant association between single nucleotide polymorphisms (SNPs) in the genomic region containing the CHRNA6 and CHRNB3 genes and tobacco behaviors. In this study, we provide support for an association between these genes and tobacco ...[more]

PMID: 18704094

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Project description:BackgroundWaterpipe tobacco (WT) smoking by young adults remains high and misperceptions are common. Product warnings can increase knowledge of harms and reduce use. The goal of this study was to test warning statements, including the FDA-required nicotine warning (prior to implementation), on young adults' thinking about harms of and discouragement from WT smoking.MethodsWe conducted a between-subjects experiment in a nationally representative telephone survey of 1152 young adults aged 18-29. Participants were randomly assigned to hear one of five warning statements and reported how much, on a 4-point scale, the warning made them think about the harms and discouraged them from WT smoking.ResultsThe sample was 36.8% female, 57.8% white, 20.2% Black, 24.1% Hispanic, with a mean age of 23.2 (SE = 0.25). Under half (43.5%) had ever smoked WT. There were significant differences among the statements on both thinking about harms (p < .0001) and discouragement (p < .0001). The FDA-required "nicotine" warning led to the lowest thinking about harms (M = 2.85, SE = 0.08) and was the least discouraging (M = 2.86, SE = 0.08), while the "100 cigarettes" warning resulted in the greatest thinking about harms (M = 3.62, SE = 0.05) and was the most discouraging (M = 3.56, SE = 0.06).ConclusionsThe nicotine warning resulted in the lowest levels of thinking about harms and discouragement from WT smoking, suggesting limited impact. However, a warning focused on comparing smoke inhalation from WT smoking to cigarettes seems promising. Warnings should cover a broad range of WT health effects, and possibly comparisons to cigarettes. Findings also have implications for the content of international waterpipe warnings.ImplicationsThis study indicates that the nicotine warning is the least effective at making young adults think about the harms of and discouraging WT smoking. The FDA and other countries should consider requiring warnings to cover a broader range of health harms, misperceptions, and possibly comparisons to cigarettes.

Project description:Cigarette smoking is a leading cause of preventable death throughout the world. Nicotine, the primary addictive compound in tobacco, plays a vital role in the initiation and maintenance of its use. Nicotine exerts its pharmacological roles through nicotinic acetylcholine receptors (nAChRs), which are ligand-gated ion channels consisting of five membrane-spanning subunits. Besides the CHRNA4, CHRNB2 and CHRNA5/A3/B4 cluster on chromosome 15, which has been investigated intensively, recent evidence from both genome-wide association studies and candidate gene-based association studies has revealed the crucial roles of the CHRNB3-CHRNA6 gene cluster on chromosome 8 in nicotine dependence (ND). These studies demonstrate two distinct loci within this region. The first one is tagged by rs13277254, upstream of the CHRNB3 gene, and the other is tagged by rs4952, a coding single nucleotide polymorphism in exon 5 of that gene. Functional studies by genetic manipulation in mice have shown that ?6*-nAChRs, located in the ventral tegmental area (VTA), are of great importance in controlling nicotine self-administration. However, when the ?6 subunit is selectively re-expressed in the VTA of the ?6(-/-) mouse by a lentiviral vector, the reinforcing property of nicotine is restored. To further determine the role of ?6*-nAChRs in the process of nicotine-induced reward and withdrawal, genetic knock-in strains have been examined, which showed that replacement of Leu with Ser in the 9' residue in the M2 domain of ?6 produces nicotine-hypersensitive mice (?6 L9'S) with enhanced dopamine release. Moreover, nicotine-induced upregulation may be another ingredient in the pathology of nicotine addiction although the effect of chronic nicotine exposure on the expression of ?6-containing receptors is controversial. To gain a better understanding of the pathological processes underlying ND and ND-related behaviors and to promote the development of effective smoking cessation therapies, we here present the most recent studies concerning the genetic effects of the CHRNB3-CHRNA6 gene cluster in ND.

Dataset Information

Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample.

Publications

Genetic association of the CHRNA6 and CHRNB3 genes with tobacco dependence in a nationally representative sample.

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