Human neuronal acetylcholine receptor A5-A3-B4 haplotypes are associated with multiple nicotine dependence phenotypes

Abstract

The CHRNA5-A3-B4 haplotypes are associated with a broad range of nicotine dependence phenotypes, but these associations are not consistently moderated by age at initial smoking.

CHRNA3 rs1051730 Genotype and Short-Term Smoking Cessation

“…However, NRT is generally well tolerated at high doses, and in the studies reported here, there was no variation in dose offered. Moreover, this explanation is also not consistent with our failure to observe a differential effect in the placebo and active arms of the Patch II study and the effect of rs1051730 reported in other studies (Baker et al, 2009;Freathy et al, 2009;Thorgeirsson & Stefansson, 2010). A second possibility is that it might be associated with cessation because it influences heaviness of smoking or tobacco dependence.…”

“…While our data on their own are inconclusive with respect to any association between variation in the CHRNA5-A3-B4 gene cluster and short-term smoking cessation in treatment-seeking smokers, it is notable that the magnitude of the effect we observed is consistent with recent evidence from a cohort study of pregnant women (Freathy et al, 2009), a community study of pregnant women (Thorgeirsson & Stefansson, 2010), and a clinical trial of treatment-seeking men and women (Baker et al, 2009). Taken together, these data are suggestive of a weak effect of genetic variation in this region on smoking cessation.…”

“…There may be important differences between this population and the wider population of smokers who attempt to stop smoking, most of whom do so spontaneously and without behavioral or pharmacological support. However, together with previous evidence (Baker et al, 2009;Freathy et al, 2009;Thorgeirsson & Stefansson, 2010), there is now evidence from five independent samples indicating that the rs1051730 variant may be weakly associated with the short-term ability to stop smoking. This may be independent of both heaviness of smoking and tobacco dependence and whether or not the individual is using NRT.…”

“…It is unclear, therefore, whether these findings can be generalized to treatment-seeking smokers and whether any association with likelihood of cessation may be modified by the use of pharmacotherapies for smoking cessation, such as NRT. However, a further study has also shown association of a haplotype containing rs1051730 with increased likelihood of relapse to smoking in a sample of smokers making a quit attempt who received either bupropion pharmacotherapy or placebo (Baker et al, 2009). We therefore investigated the potential association of rs1051730 genotype with smoking cessation in two cohorts of treatment-seeking smokers.…”

Translational Research in Nicotine Dependence

“…A number of recent GWAS and pathway-based studies have identified SNPs in this gene cluster associated with heaviness of smoking and/or nicotine dependence (Berrettini et al 2008;Bierut et al 2007;Caporaso et al 2009;Saccone et al 2007;Thorgeirsson and Stefansson 2008;Thorgeirsson et al 2010). Other aspects of nicotine dependence, such as nicotine tolerance, craving, withdrawal severity, and inability to stop smoking, have also been associated with CHRNA5-CHRNA3-CHRNB4 SNPs (Baker et al 2009). However, although this highly reproducible finding implicates this gene cluster in various aspects of nicotine dependence, whether it predicts cessation rates is unclear.…”