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 ¼ 0.007 in Caucasians). SNPs in CHRNB3 were found to be associated with the number of quit attempts (p ¼ 0.0024). Together these results further implicate the region downstream of CHRNA6 and the region upstream of CHRNB3 in risk of nicotine dependence.

Association of nicotinic acetylcholine receptor subunit α4 polymorphisms with nicotine dependence in 5500 Germans

“…1 The addictive potential of the nicotine contained in cigarettes has been firmly established, 2 but individual and especially genetic differences regarding susceptibility to nicotine addiction, which could give crucial hints to drug discovery, are not well understood. 3 Nicotinic acetylcholine receptor subunit genes are obvious candidates for genetic risk factor investigations into smoking-related traits, for example see Hoft et al 4 The a4-subunit of the pentameric nicotinic receptor, which is especially frequent as part of high-affinity receptors in the central nervous system, 5 has yielded particularly interesting results in the few studies available to date. Single-nucleotide polymorphisms (SNPs) or haplotypes of the coding gene CHRNA4 have been implicated as predictors of nicotine addiction in family-based analyses 6,7 and have been reported to be associated with smoking cessation in a clinical trial.…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…When unrelated singletons (in the whole sample or within a current frequent smokers sub-population only) were examined for genetic association with ND, nominal association was detected in these two SNPs, as well as in CHRNB3 rs7004381 and rs4950 and CHRNA6 rs892413. 109 Four SNPs in the CHRNB3 gene (rs7004381, rs4950, rs4953 and rs13280604) and one CHRNA6 SNP, rs2304297, were associated with number of quit attempts, regardless of ethnicity. Only the association of rs7004381 with quit attempts survives Bonferonni correction.…”

“…Only the association of rs7004381 with quit attempts survives Bonferonni correction. 109 In the Stevens et al 90 study, which is described in detail above, two SNPs were nominally significantly associated with heavy smoking (rs7012713 in CHRNB3 and rs7828365 in CHRNA6), but both did not survive correction for multiple testing. Nominal associations of rs9298629 (P = 0.035, genotype) and rs1072003 (P = 0.053, genotype) with severity of ND were reported by Greenbaum et al, 81 in a small sized case-control study of 11 nAChRs gene among female Israeli students aged 20-30 years, divided into high (n = 127) and low ND (n = 115) groups.…”

“…Strong limitations of this study are reliance on retrospective reports of young individuals, multiple testing and the possibility that other substances were tried in the same period of experiencing tobacco and alcohol. 108 Hoft et al 109 investigated the association of eight SNPs in the CHRNA6-CHRNB3 cluster with smoking behavior in a representative sample of US households, which included 1051 participants, nearly half of them members of sibling pairs. 109 ND was assessed using DSM-IV criteria and individuals who endorsed three or more of the seven dependence symptoms were considered dependent.…”

“…108 Hoft et al 109 investigated the association of eight SNPs in the CHRNA6-CHRNB3 cluster with smoking behavior in a representative sample of US households, which included 1051 participants, nearly half of them members of sibling pairs. 109 ND was assessed using DSM-IV criteria and individuals who endorsed three or more of the seven dependence symptoms were considered dependent. The second phenotype was the number of unsuccessful quit attempts.…”