地方性砷中毒（简称地砷病）是一种危害严重的地方病。无机砷的代谢过程及其对基因组DNA甲基化的影响，在砷的致癌机制中起着重要作用。无机砷既可以引起DNA高甲基化，又可引起DNA低甲基化，其导致DNA甲基化异常与砷的毒性作用关系密切。本项目采用人群流行病学、表观遗传学和生物信息学多学科交叉研究手段，利用HumanMethylation27人类全基因组甲基化芯片技术，对不同水砷浓度暴露人群的CpG岛、miRNA启动子区域和非编码区等27578个CpG位点的DNA甲基化水平以及12700个基因的表达水平进行检测，分析不同水砷浓度暴露对DNA甲基化水平的影响差异，筛选特异性DNA甲基化位点和差异表达基因，分析砷暴露人群基因的甲基化模式与基因表达沉默模式的关系，阐明DNA甲基化同地砷病发病及个体尿砷代谢模式的关系，从表观遗传学角度探讨无机砷对人体的远期毒性作用，为砷致癌的分子机制研究提供依据。

Endemic arsenic poisoning (endemic arsenism) is a serious endemic disease. The metabolic processes of inorganic arsenic and its effects on human genome DNA methylation play an important role in arsenic carcinogenesis mechanism. Inorganic arsenic can cause both high and low level DNA methylation of human genome, this kind of abnormal DNA methylation is closely related with the toxic effects of inorganic arsenic. With the methods of epidemiology survey and the technology of epigenetics and bioinformatics, large-scale detection and analysis of human genome DNA methylation in the population exposed to different arsenic concentrations in drinking water are going to be carried out in this project using HumanMethylation27 human genome methylation chip. The 27578 DNA methylation CpG sites include CpG islands and the different methylation sites between the tumor and normal cells and the sites of miRNA promoter region and the non-coding region. The aims of this project is to analyze the effects of inorganic arsenic of different concentrations in drinking water on human genome DNA methylation, to analyze the relationship between the DNA methylation patterns and expression level of 12700 genes in chip, and to illuminate the relationship between DNA methylation and endemic arsenism as well as individual urinary arsenic metabolism model. The results of this project will provide the basis for the study of arsenic carcinogenesis molecular mechanism from the epigenetic aspects.

地方性砷中毒是一种危害严重的地方病。无机砷的甲基化代谢过程及其对基因组DNA甲基化的影响，在砷的致癌机制中起着重要作用，其导致DNA甲基化异常与砷的毒性作用关系密切。本项目采用人群流行病学、遗传学、表观遗传学和生物信息学多学科交叉研究手段，采用SNPscan分型技术对我国三个主要的高砷饮水型砷中毒病区1040个样本的SNP位点进行分型检测，分析了与无机砷甲基化代谢密切相关基因25个位点的多态性与地砷病易感性及尿砷甲基化代谢之间的关系；检测分析了MTHFR、MTR和ERCC 基因SNP 位点多态性与地方性砷中毒易感性的关系；采用Illunina Miseq 2X260bp平台进行双向测序，对不同水砷浓度暴露人群启动子区域CpG位点的DNA甲基化水平进行检测，分析砷暴露人群基因的甲基化模式的改变及影响。结果表明，GSTO1基因rs11191979位点等位基因C、rs2164624位点等位基因A、rs4925位点等位基因A、GSTO2基因rs156697位点AG基因型、rs2297235位点等位基因G、PNP基因rs3790064位点等位基因G是发生地方性砷中毒的风险等位基因；携带ERCC2基因rs13181位点等位基因C的个体与携带AA基因型的个体相比，会增加砷中毒致发生的风险；高水砷暴露会引起MGMT 、ERCC2基因DNA甲基化模式的变化，主要包括基因组整体甲基化水平和启动子区CpG岛局部甲基化水平的异常升高；暴露群体中MGMT和ERCC2基因启动子区高甲基化模式的个体，尿砷中MMA%相对较高、DMA%和SMI相对较低，增大了患有地砷病的风险，MGMT和ERCC2基因启动区高甲基化可能是砷中毒发生发展的早期事件；停饮高砷水十年后，MGMT基因启动子区CpG岛甲基化异常水平仍然存在，表明无机砷具有较强的远期毒性作用。上述人群研究结果为砷致癌分子机制研究提供了重要的基础资料。