Biological mechanisms underlying inherited genetic effects on arsenic metabolism

项目摘要/摘要 70多个国家的1亿多人饮用被无机物污染的水 砷(IAS)，一种与健康风险有关的毒物，包括癌症、心血管疾病 疾病，以及认知发展受损。对IAS毒性的易感性部分 由影响个体代谢IAS能力的遗传因素决定的，IAS是一个过程 这有助于从体内(通过尿液)去除砷。流行病学的一个主要焦点 对IAS暴露的研究一直在识别影响砷的遗传遗传变异 代谢效率(AME)，以便(1)能够基于毒性对个体进行分类 风险和(2)阐明AME个体间差异的生物学机制 告知制定可降低毒性风险的干预措施。虽然之前的研究已经 成功识别出与AME和毒性风险相关的遗传变异，它们的生物学 机制还没有完全弄清楚。该项目的长期目标是利用新兴的 和创新的基因编辑方法，从功能上阐明 SNPs会影响人体细胞的砷代谢。这项建议的目的是 从功能上定义我们先前建立的因果FTCD和AS3MT SNP 在暴露于砷的人群中，AME与AME密切相关。我们的中央 假设是(1)FTCD SNP rs61735836上的次要等位基因因此改变了酶的活性 减少砷的甲基化；(2)致病的AS3MT SNP(S)降低AS3MT RNA和 蛋白质表达，也导致砷甲基化减少。完成这些研究 将确定一个机制框架，用于调查与砷有关的更多SNPs 新陈代谢。识别影响AME的因果变量并了解其机制 将与接触砷影响风险的许多疾病广泛相关，因为 这些单核苷酸多态可能会影响体内砷的剂量。

PROJECT SUMMARY/ABSTRACT Over 100 million people in over 70 countries consume water that is contaminated with inorganic arsenic (iAs), a toxicant that has been linked to health risks that include cancer, cardiovascular disease, and impaired cognitive development. Susceptibility to iAs toxicity is partially determined by genetic factors that influence an individual’s ability to metabolize iAs, a process that facilitates the removal of arsenic from the body (in urine). A major focus of epidemiological research on iAs exposure has been identifying inherited genetic variation that influences arsenic metabolism efficiency (AME) in order to (1) enable classification of individuals based on toxicity risk and (2) elucidate the biological mechanism underlying inter-individual differences in AME to inform the development of interventions that reduce toxicity risk. While prior studies have successfully identified genetic variants associated with AME and toxicity risk, their biological mechanisms are not fully understood. The long-term goal of this project is to utilize emerging and innovative gene-editing approaches to functionally elucidate the mechanisms by which SNPs impact cellular arsenic metabolism in humans. The objective of this proposal is to functionally define the causal FTCD and AS3MT SNPs that we have previously established as strongly associated with AME in human populations exposed to arsenic. Our central hypotheses are (1) the minor allele at FTCD SNP rs61735836 modifies enzymatic activity thus reducing arsenic methylation and (2) the causal AS3MT SNP(s) reduce AS3MT RNA and protein expression, also leading to reduced arsenic methylation. Completion of these studies will define a mechanistic framework for the investigation of additional SNPs related to arsenic metabolism. Identifying causal variants that affect AME and understanding their mechanisms will be broadly relevant to the many diseases for which arsenic exposure impacts risk, because these SNPs likely impact internal dose of arsenic.