Leventhal Adam M, Lee Wonho, Bergen Andrew W, Swan Gary E, Tyndale Rachel F, Lerman Caryn, Conti David V
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA; Department of Psychology, University of Southern California, Los Angeles, CA 90033, USA.
Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Drug Alcohol Depend. 2014 May 1;138:109-17. doi: 10.1016/j.drugalcdep.2014.02.016. Epub 2014 Mar 5.
Genetic influences on smoking cessation treatment outcome may be affected by pretreatment patient characteristics. Nicotine dependence is arguably the most salient clinical factor in smoking cessation.
In this secondary analysis of clinical trial data (N=793), we examined nicotine dependence severity as a moderator of the effects of 1198 single nucleotide polymorphisms (SNPs) in 53 biologically-relevant gene regions on smoking cessation outcomes. P-values were adjusted to account for multiple correlated SNPs within a gene region; corrected system-wide significance was 5 × 10(-4).
SNP × nicotine dependence interactions reached region-wide significance for several SNPs in the Dopamine Beta Hydroxylase (DBH) locus (0.0005<Adjusted-P<0.05), including rs1541333, which reached system-wide significance for predicting end of treatment (EOT) abstinence (Adjusted-P=0.0004). A haplotype including 6 DBH SNPs predicted abstinence at EOT (OR=1.7, P=0.001) and 6-month follow-up (OR=1.6, P=0.008) in those with high nicotine dependence (n=526) but not in those with low dependence (n=227). The DBH signal observed here may be distinct from a previously reported genome-wide significant signal for former smoking status and from the principal haplotype associated with plasma dopamine beta-hydroxylase activity. A haplotype within the Chromosome 15 Nicotinic Acetylcholine Receptor gene region predicted abstinence at EOT in those with high (OR=2.0, P=0.0004) but not low (P=0.6) dependence in post hoc analyses.
Considering pre-treatment nicotine dependence level may optimize the prediction of genetic influences on cessation outcomes. If replicated, results like these may inform prognosticative genomic screening panels designed to identify smokers at high risk of relapse when coupled with severe nicotine dependence.
基因对戒烟治疗结果的影响可能受到治疗前患者特征的影响。尼古丁依赖可以说是戒烟中最显著的临床因素。
在对临床试验数据（N = 793）的这项二次分析中，我们将尼古丁依赖严重程度作为53个生物学相关基因区域中1198个单核苷酸多态性（SNP）对戒烟结果影响的调节因素进行了研究。对P值进行了调整，以考虑基因区域内多个相关的SNP；全系统校正显著性为5×10⁻⁴。
对于多巴胺β羟化酶（DBH）基因座中的几个SNP，SNP×尼古丁依赖相互作用达到全区域显著性（0.0005 < 校正P < 0.05），包括rs1541333，其在预测治疗结束（EOT）时戒烟方面达到全系统显著性（校正P = 0.0004）。一个包含6个DBH SNP的单倍型在高尼古丁依赖者（n = 526）中预测了EOT时的戒烟（OR = 1.7，P = 0.001）和6个月随访时的戒烟（OR = 1.6，P = 0.008），但在低依赖者（n = 227）中未观察到。此处观察到的DBH信号可能与先前报道的关于既往吸烟状态的全基因组显著性信号以及与血浆多巴胺β羟化酶活性相关的主要单倍型不同。在事后分析中，15号染色体烟碱型乙酰胆碱受体基因区域内的一个单倍型在高依赖者（OR = 2.0，P = 0.0004）而非低依赖者（P = 0.6）中预测了EOT时的戒烟。
考虑治疗前尼古丁依赖水平可能会优化对基因对戒烟结果影响的预测。如果得到重复验证，这样的结果可能为旨在识别与严重尼古丁依赖相关的高复发风险吸烟者的预后基因组筛查面板提供信息。
