Biological mechanisms underlying inherited genetic effects on arsenic metabolism

项目总结/摘要 70多个国家的1亿多人饮用受无机污染的水 砷（iAs），一种与健康风险有关的有毒物质，包括癌症，心血管疾病， 疾病和认知发育受损。对iAs毒性的敏感性部分 由影响个体代谢iAs的能力的遗传因素决定，iAs是一个过程， 促进砷从体内（尿液中）排出。流行病学的一个主要焦点 对砷暴露的研究已经确定了影响砷的遗传变异 代谢效率（AME），以便（1）能够基于毒性对个体进行分类 （2）阐明AME个体间差异的生物学机制， 为制定减少毒性风险的干预措施提供信息。虽然先前的研究 成功鉴定了与AME和毒性风险相关的遗传变异， 机制尚未完全理解。该项目的长期目标是利用新兴的 和创新的基因编辑方法，以功能性地阐明 SNPs影响人类细胞砷代谢。这项建议的目的是 在功能上定义了我们以前建立的因果FTCD和AS 3 MT SNP， 与暴露于砷的人群中的AME密切相关。我们的中央 假设是（1）FTCD SNP rs61735836处的次要等位基因改变酶活性， 减少砷甲基化和（2）致病性AS 3 MT SNP减少AS 3 MT RNA， 蛋白质表达，也导致砷甲基化减少。完成这些研究 将定义一个机制框架，用于研究与砷相关的其他SNPs 新陈代谢.识别影响AME的因果变异并了解其机制 将与砷暴露影响风险的许多疾病广泛相关，因为 这些SNPs可能影响砷的体内剂量。

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.