Tyndale Rachel F, Zhu Andy Z X, George Tony P, Cinciripini Paul, Hawk Larry W, Schnoll Robert A, Swan Gary E, Benowitz Neal L, Heitjan Daniel F, Lerman Caryn
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Division of Brain & Therapeutics, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2015 May 26;10(5):e0128109. doi: 10.1371/journal.pone.0128109. eCollection 2015.
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.
CHRNA5 - A3 - B4基因变体rs16969968、rs588765和rs578776一直与吸烟者的烟草消费相关，但与戒烟的关联则不太一致。在报告与戒烟有显著关联的研究中，一些研究在接受安慰剂治疗的吸烟者中观察到了这种效应，而在另一些研究中，效应则出现在接受活性药物治疗（安非他酮和尼古丁替代疗法）的吸烟者中。因此，CHRNA5 - A3 - B4是否是优化戒烟的有用标志物仍不清楚。我们使用来自654名接受安慰剂、尼古丁贴片或伐尼克兰治疗的白人吸烟者的数据，研究了CHRNA5 - A3 - B4基因变体是否与戒烟结果相关，以及是否存在显著的基因 - 治疗或单倍型 - 治疗相互作用。尽管重复了之前与基线烟草消费的关联，但我们未观察到CHRNA5 - A3 - B4基因变体与戒烟之间存在显著关联。在治疗结束时，rs16969968 [GG与GA + AA]在安慰剂组、贴片组和伐尼克兰组中对戒烟的效应大小分别为OR = 0.66（P = 0.23）、OR = 1.01（P = 0.99）和OR = 1.30（P = 0.36）；rs588765 [CC与CT + TT]分别为OR = 0.96（P = 0.90）、OR = 0.84（P = 0.58）和OR = 0.74（P = 0.29）；rs578776 [GG与GA + AA]对戒烟的效应大小分别为OR = 1.02（P = 0.95）、OR = 0.75（P = 0.35）和OR = 1.20（P = 0.51）。此外，我们未观察到使用CHRNA5 - A3 - B4单倍型（由rs16969968和rs588765构建）与戒烟之间存在关联，也未观察到任何显著的基因 - 治疗相互作用，无论是否调整尼古丁代谢率（所有P>0.05）。我们也未观察到与6个月或12个月戒烟有显著的基因关联。总之，在这项临床试验中，我们未发现CHRNA5 - A3 - B4基因变体与戒烟率之间存在关联；然而，正如预期的那样，重复了与基线烟草消费的显著关联。我们的数据表明，CHRNA5 - A3 - B4基因变体与戒烟之间不存在强烈关联，不太可能用于临床优化白人吸烟者的戒烟药物治疗。
