砷代谢相关酶基因多态性对其甲基化代谢及中毒发病风险的影响

Inorganic arsenic is methylated into MMA and DMA in the liver. MMA is the most toxic form among arsenic metabolites, especially trivalent MMA. Since MMA%, which is dependent on the individual methylation capability, is reported to be positively correlated with arsenic related symptoms such as skin lesions and tumor, therefore, individual methylation capability is associated with arsenic related disease. It has been reported that genetic (gene polymorphism) and environmental (diet, smoking, alcohol consumption) factors may influence the individual methylation capability, although the mechanism is still unclear. Most of the current researches concerning the influencing factors of individual methylation capability have such limitations as single factor and single gene. Few involved multiple factors and multiple genes. In this study, we detected 13 sites of gene polymorphism from 8 genes, which is involved in the metabolic pathway of arsenic methylation, and discussed the impacts of gene polymorphism on the individual capability of arsenic methylation and the risk of arsenic poisoning by considering both of the effects of heredity and environment. Our findings will be useful in the screening of the population who is at higher risk to arsenic related diseases, and provide safe and convenient measures for the protection against arsenic poisoning by guiding the high risk population with proper diet and personal habits, which will decrease the risk of arsenic poisoning in the population.

无机砷（iAs）在肝脏进行甲基化代谢，生成一甲基砷（MMA）及二甲基砷（DMA）。MMA，特别是三价MMA毒性最高。MMA%与人群皮肤损伤程度、肿瘤发生率呈显著正相关。由于MMA%的高低取决于与个体对砷的甲基化代谢能力，因此，个体对砷的甲基化代谢能力与砷相关疾病的发生具有直接联系。影响砷甲基化代谢的机制仍不清楚，目前研究认为可能包括遗传因素（基因多态性）和环境因素（饮食、吸烟、饮酒）。但是，已有的相关报道一般仅涉及单基因、单因素研究，缺乏多基因、多因素的全面分析。本项目着眼于与砷甲基化代谢密切相关的8个基因、13个位点的多态性，在充分考虑环境因素影响的基础上，深入探讨遗传因素对砷甲基化代谢及砷中毒发病风险的影响。研究结果有助于在砷暴露人群中发现对砷危害更为敏感的高风险人群，并通过指导饮食习惯和生活行为方式等手段，为该群体提供降低砷中毒发病风险的安全、简便的防护措施。

本研究综合探讨了环境因素（叶酸、维生素B12）、个体因素（吸烟、饮酒）及遗传因素（与砷甲基化代谢密切相关的8个酶基因的多态性）对砷甲基化代谢及砷中毒发病风险的影响。研究发现，叶酸及维生素B12缺乏、吸烟及饮酒、尿HCY水平高均可增加砷中毒的发病风险；MTHFR的RS1801131、RS9651118及MTRR的RS1801394突变型个体可能是砷暴露的高危人群；砷暴露可引起脂代谢指标HDL水平显著降低、TC/HDL水平显著增高，这可能是砷致心血管疾病发生的基础；MMA%增高及SMR水平降低可作为砷暴露者发生中毒危险性增高的生物标志物。.研究结果提示，砷暴露地区人群可通过改变膳食习惯（补充足量的叶酸及维生素B12）、改变生活习惯（戒烟戒酒）等简单的外源性干预手段降低砷中毒发病风险。对于生活在砷暴露地区有特定基因型的砷中毒高危群体更应提早采用上述手段进行早期预防，从而降低砷中毒的发病风险。