Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
Neuropsychopharmacology. 2010 May;35(6):1374-82. doi: 10.1038/npp.2010.7. Epub 2010 Feb 10.
The ability to quit smoking is heritable, yet few genetic studies have investigated prospective smoking cessation. We conducted a systems-based genetic association analysis in a sample of 472 treatment-seeking smokers of European ancestry after 8 weeks of transdermal nicotine therapy for smoking cessation. The genotyping panel included 169 single-nucleotide polymorphisms (SNPs) in 7 nicotinic acetylcholine receptor subunit genes and 4 genes in the endogenous cholinergic system. The primary outcome was smoking cessation (biochemically confirmed) at the end of treatment. SNPs clustered in the choline acetyltransferase (ChAT) gene were individually identified as nominally significant, and a 5-SNP haplotype (block 6) in ChAT was found to be significantly associated with quitting success. Single SNPs in ChAT haplotype block 2 were also associated with pretreatment levels of nicotine dependence in this cohort. To replicate associations of SNPs in haplotype blocks 2 and 6 of ChAT with nicotine dependence in a non-treatment-seeking cohort, we used data from an independent community-based sample of 629 smokers representing 200 families of European ancestry. Significant SNP and haplotype associations were identified for multiple measures of nicotine dependence. Although the effect sizes in both cohorts are modest, converging data across cohorts and phenotypes suggest that ChAT may be involved in nicotine dependence and ability to quit smoking. Additional sequencing and characterization of ChAT may reveal functional variants that contribute to nicotine dependence and smoking cessation.
戒烟能力是可遗传的，但很少有遗传研究调查前瞻性戒烟。我们对 472 名寻求治疗的欧洲血统吸烟者进行了一项基于系统的遗传关联分析，这些吸烟者在接受 8 周的透皮尼古丁戒烟治疗后。基因分型面板包括 7 个烟碱型乙酰胆碱受体亚基基因和内源性胆碱能系统中的 4 个基因中的 169 个单核苷酸多态性（SNP）。主要结局是治疗结束时的戒烟（生物化学确认）。胆碱乙酰转移酶（ChAT）基因中的 SNP 聚类被单独确定为名义上显著，并且 ChAT 中的 5-SNP 单倍型（块 6）被发现与戒烟成功显著相关。ChAT 单倍型块 2 中的单个 SNP 也与该队列中尼古丁依赖的预处理水平相关。为了在非治疗寻求者队列中复制 ChAT 单倍型块 2 和 6 中的 SNP 与尼古丁依赖的关联，我们使用了来自代表欧洲血统 200 个家庭的 629 名吸烟者的独立基于社区的样本中的数据。多个尼古丁依赖测量的 SNP 和单倍型关联均具有统计学意义。尽管两个队列中的效应大小都较小，但两个队列和表型的汇聚数据表明 ChAT 可能与尼古丁依赖和戒烟能力有关。ChAT 的额外测序和特征描述可能会揭示导致尼古丁依赖和戒烟的功能变体。
