Evidence of the involvement of the α5, α3, and β4 subunits in nACh receptor desensitization rates, calcium permeability, and response to nicotine (Gerzanich et al. 1998; Tapia et al. 2007), as well as the association of the CHRNA5-CHRNA3-CHRNB4 gene cluster with nicotine dependence phenotypes, has led to studies of the role of key SNPs in withdrawal symptoms and smoking cessation. In a case–control study of 1,446 current versus former smokers, no evidence was found for associations of SNPs in the CHRNA5-CHRNA3-CHRNB4 gene cluster with retrospective smoking cessation (Breitling et al. 2009a). Similarly two independent nAChR systems-based analyses found no evidence for associations of SNPs in this gene cluster with prospective smoking cessation in participants treated with transdermal NRT or bupropion (Conti et al. 2008; Ray et al. 2010). However, data published by Baker and others provides evidence for association of CHRNA5-CHRNA3-CHRNB4 haplotypes with tolerance, craving, and loss of control, but only among individuals who began smoking early in life, suggesting that the genetic risk may only occur with early tobacco exposure (Baker et al. 2009). The CHRNA5-CHRNA3-CHRNB4 haplotypes are also
