基于网络生物学技术探讨尼古丁依赖关键基因变异对戒烟成功的影响

Based on the network biologic technology and community-based case control study, and referred to HapMap data platform for Chinese people, the TagSNPs will be screened and selected from the key genes related to nicotine dependence (ND) by using software such as Haploview. The haplotype constructed using TagSNPs will represent the whole information in one gene, and all the haplotypes in the key genes related to ND will be used as the genetic markers set of the subject; The psychosocial factors and the factors screened by multiple stepwise logistic regression from the individual characteristics will be jointly used as the clinical markers set of the subject; The elements in both genetic and clinical markers sets will be served as the nodes that are used to develop Bayesian network (BN). The key nodes or the combination of the key nodes related to smoking cessation success in BN will be identified via the analysis on the characteristics of topology of the BN. The key genes related to ND, or the combination of key genes related to ND with psychosocial factors, which have significant effect on the smoking cessation success, will be screened and confirmed by BN reasoning function; The BN model will be systemically evaluated by using cross validation and indices for diagnostic test. Based on above analyses, the effect of key genes related to ND on smoking cessation success will be assessed, and the interaction between key genes related to ND and psychosocial factors on smoking cessation success will be evaluated. This will provide the basis for the effective intervention on smoking cessation.

依据网络生物学技术，采用病例对照研究，参照HapMap中国人群数据平台，应用Haploview从尼古丁依赖（ND）各关键基因SNPs中筛选TagSNPs，并构建单体型作为整体基因信息，构成研究对象遗传标记集；利用宿主心理、社会因素，以及经多元逐步Logistic回归对个体特征筛选出的有显著意义的变量共同构成研究对象临床标记集；以遗传标记集和临床标记集中的各元素为节点，构建遗传因素、宿主与环境因素间贝叶斯网络模型；分析网络的拓扑结构特征，以鉴定那些与戒烟成功相关的关键节点和节点通路组合；借助贝叶斯网络推理功能，证实和筛选与戒烟成功相关的ND关键基因、基因间、及与宿主和环境因素的组合；利用交叉验证法及诊断实验评价指标，对所确定的网络模型进行系统评价。据此，可阐明ND关键基因变异对戒烟成功的影响；评价ND关键基因与宿主、社会环境因素之间在戒烟成功中的交互效应；为有效的戒烟干预提供依据。

虽然众多研究显示，基因变异是吸烟依赖与戒烟成功的重要影响因素。然而，吸烟依赖与其它物质依赖一样，并非完全是躯体的依赖，心理依赖同样具有重要作用。本项目利用以人群为基础的病例对照研究设计，依据流行病学病因网原理，应用加权等位基因分数反映尼古丁成瘾与依赖各关键基因的整体基因信息，结合个体及环境因素，探讨尼古丁成瘾与依赖关键基因变异对戒烟成功的影响；研究个体、社会环境因素共同存在下，遗传因素对戒烟成功的影响程度；评价尼古丁成瘾及依赖关键基因与个体、社会环境因素之间在戒烟成功中的交互效应。结果显示，烟碱乙酰胆碱受体基因系统（CHRNA3、CHRNA5）和尼古丁代谢系统基因（POR）与戒烟成功显著相关；多巴胺奖赏通路系统（COMT、DRD2）加权等位基因分数与戒烟成功有显著负相关；而ANKK1、 SLC6A3、DRD4加权等位基因分数与戒烟成功有显著正相关。表明遗传因素对戒烟成功具有显著影响。贝叶斯网络分析显示，基因、个体、心理因素共同影响戒烟成功与否。在每天吸烟量高、吸烟年数长、吸烟危害认知程度低、拒烟自我效能水平低的吸烟者中，只有45.69%成功戒烟。优势分析结果显示，上述因素对戒烟成功的影响作用（标准化优势权重）由大到小依次为吸烟严重程度因素（38%）、个体因素（37%）、基因因素（18%）、心理因素（7%），可见影响戒烟成功的首要因素是吸烟严重程度因素，而遗传因素在戒烟成功与否中的作用相对较小。交互作用分析显示，多巴胺转运体基因SLC6A3与尼古丁依赖程度以及5-羟色胺系统基因-基因交互作用对戒烟成功有显著影响。上述研究结果不但丰富了该相关领域的研究内容，而且为将来人群控烟干预措施的制定提供了理论依据。