Abstract
CHRNA5-A3-B4 variants, rs16969968, rs588765 and rs578776, are consistently associated with tobacco consumption among smokers, but the association with smoking cessation is less consistent. Among the studies that reported significant associations with cessation, the effects were observed in smokers treated with placebo treatment in some studies and conversely in those receiving active pharmacological therapy (bupropion and nicotine replacement therapies) in others. Thus, it remains unclear whether CHRNA5-A3-B4 is a useful marker for optimizing smoking cessation. Using data from 654 Caucasian smokers treated with placebo, nicotine patch or varenicline, we investigated whether CHRNA5-A3-B4 variants were associated with smoking cessation outcomes, and whether there were significant genotype-by-treatment or haplotype-by-treatment interactions. We observed no significant associations between CHRNA5-A3-B4 variants and smoking cessation, despite replicating previous associations with baseline tobacco consumption. At end of treatment the effect size on smoking cessation in the placebo, patch and varenicline groups for rs16969968 [GG vs. GA+AA] was OR = 0.66 (P = 0.23), OR = 1.01 (P = 0.99), and OR = 1.30 (P = 0.36) respectively, of rs588765 [CC vs. CT+TT] was OR = 0.96 (P = 0.90), OR = 0.84 (P = 0.58), and OR = 0.74 (P = 0.29) respectively, and for rs578776 [GG vs. GA+AA] on smoking cessation was OR = 1.02 (P = 0.95), OR = 0.75 (P = 0.35), and OR = 1.20 (P = 0.51) respectively. Furthermore, we observed no associations with cessation using the CHRNA5-A3-B4 haplotype (constructed using rs16969968 and rs588765), nor did we observe any significant genotype-by-treatment interactions, with or without adjusting for the rate of nicotine metabolism (all P>0.05). We also observed no significant genetic associations with 6 month or 12 month smoking abstinence. In conclusion, we found no association between CHRNA5-A3-B4 variants and smoking cessation rates in this clinical trial; however, as expected, significant associations with baseline tobacco consumption were replicated. Our data suggest that CHRNA5-A3-B4 gene variants do not exhibit a robust association with smoking cessation and are unlikely to be useful for clinically optimizing smoking cessation pharmacotherapy for Caucasian smokers.
Highlights
Smoking is a leading cause of premature death; world-wide about 6 million deaths each year can be attributed to smoking [1]
The CHRNA5-A3-B4 haplotype was defined by rs16969968 and rs588765. * Cotinine is a part of nicotine metabolite ratio (NMR), and cotinine levels are not directly comparable in people with different NMR [48], NMR was not included in the cotinine analysis. doi:10.1371/journal.pone.0128109.t002
We report a lack of association between CHRNA5-A3-B4 genetic variants/haplotype and end of treatment smoking cessation outcomes in Caucasian smokers despite the expected significant association between CHRNA5-A3-B4 genetic variants and baseline smoking behaviors
Summary
Smoking is a leading cause of premature death; world-wide about 6 million deaths each year can be attributed to smoking [1]. Genetic mapping studies indicate that three independent loci within CHRNA5-A3-B4 are associated with cigarette consumption and nicotine dependence in Caucasians [11, 12] These independent loci can be represented by rs16969968 and correlated SNPs (sometimes referred to as “Bin A” or “Locus 1”), rs588765 and correlated SNPs (sometimes referred to as “Bin B” or “Locus 3”), and rs578776 and correlated SNPs (sometimes referred to as “Bin C” or “Locus 2”). The impact of these independent loci on cigarette consumption and nicotine dependence has been consistently replicated, but whether these variants predict smoking cessation outcomes is less clear and is the focus of this investigation [11, 12]
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