中国汉族人群尼古丁依赖的易感基因位点关联分析及易感基因功能研究

Consist but indirect evidence has implicated genetic factors in smoking behavior.Previous genome-wide association studies(GWAS)and GWAS meta analyses in european and american crowd identified multiple loci associted with smoking behavior.Notely,the several loci identified were each associated with only one specific smoking phenotype.The findings suggests that separate genetic loci contribute modestly to phenotypic variability in each aspect of smoking behavior.We propose to identify multiple susceptibility loci as being associated with smoking behavior in Chinese Han group.The findings will identify possiblely the strongest associatied loci with nicotine dependence of Chinese,which,in turn,may have implications for the way in which smoking cessation therapies and tobacco control efforts are designed and targeted.The missense variant rs6265 located in BDNF exceeded genome wide significence for smoking initiation.We designed three aspects experiment to investigate the molecular mechanisms of nicotine dependence.The first, We proposed to detected the expression level of the BDNF protein in serum, the second, measure the level of DNA methylation of BDNF from primary cultured hippocampus neurons after treated by nicotine, the finally, electrophysiological change of primary cultured hippocampus neurons which by thransfect wild type or variant BDNF gene after treatment by nicotine.

遗传因素可能在吸烟行为中起着重要作用。多项欧美国家的全基因组关联研究（Genome-wide association studies, GWAS）及元分析（meta analysis）鉴定了某些与吸烟关联的SNPs，表明不同基因与吸烟行为相关。本项目拟通过对中国汉族吸烟人群与多个尼古丁依赖易感基因的关联分析，验证中国人群中与尼古丁依赖相关的基因；同时对多个基因进行研究，可能发现其中有最强相关的易感基因，并为解释尼古丁依赖的病因学、寻找干预和治疗的靶点提供线索。另一方面，BDNF基因rs6265位点已被证实与吸烟起动有较强关联，本项目拟通过检测中国汉族吸烟人群血清中BDNF蛋白表达水平与rs6265等位基因的关联，以及不同等位基因型经尼古丁处理后BDNF基因甲基化水平、蛋白表达水平、细胞电生理等的变化，探讨rs6265位点在中国人群中与吸烟起动的关联以及可能影响BDNF基因功能的分子机制。

遗传因素可能在吸烟行为中起着重要作用。多项欧美国家的全基因组关联研究及元分析鉴定了某些与吸烟关联的SNPs位点，表明不同基因与吸烟行为存在关联。本项目采集了1141例2013-2014年来中心体检的中国汉族吸烟人群的外周血样本并进行DNA提取，同时采集血常规、肝肾功能、血糖、血脂、骨密度等人体生化指标以及相关检测指标数据，进行了个体资料采集，并进行Fagerstrom尼古丁依赖问卷调查，通过应用SNP质谱分型结合DNA测序技术在样本中进行尼古丁依赖发生机制通路中的多个易感基因的30个SNPs位点关联分析，数据结果正在进一步分析整理中。通过本研究建立了中国汉族吸烟人群的临床资料数据库以及外周血DNA库；完成了尼古丁依赖发生机制通路上的相关易感基因的多位点关联分析，建立了尼古丁依赖易感基因的分子分型诊断平台。