Genetic underpinning of diabetes associated with arsenic exposure

项目概要 无机砷 (iAs) 是一种常见的饮用水和食品污染物，导致数亿人中毒 世界各地的个人，包括美国。已经确定，长期接触 iAs 会导致 与 2 型糖尿病 (T2D) 的风险相关，iAs 代谢成甲基化形式是一个关键 确定人类 T2D 风险的重要组成部分。 iAs 的甲基化由砷催化 甲基转移酶（AS3MT）。虽然使用全基因组方法的研究已经确定了 AS3MT作为决定iAs代谢个体间差异的主要遗传因素，遗传因素 iAs 相关 T2D 易感性的基础从未得到系统研究，因此 关键的知识差距。我们团队进行的群体研究结果表明，多态性 AS3MT 和其他几个参与 iAs 代谢或葡萄糖稳态调节的基因可能 也会增加 T2D 风险。该项目将使用多样性远交（DO）和协作杂交（CC） 小鼠种群来解决这一知识差距。该提案的中心假设是多重 基因和单倍型（除 As3mt 外）将与 iAs 相关的糖尿病表型相关 曝光。我们将首先检查一大群暴露于 iAs。将在尿液和肝脏中评估 iAs 代谢的差异。将对小鼠进行基因分型和遗传 绘图将导致与风险相关的数量性状基因座 (QTL) 和创始人单倍型的识别 和保护性等位基因。性别、砷暴露剂量和基因表达作为单倍型中介的作用 然后使用 QTL 上具有对比等位基因的 CC 菌株建立表型关系。最后， 我们将评估小鼠群体中确定的风险位点在 iAs 个体间差异中的作用 现有人类队列中的代谢和代谢表型，其中 iAs 暴露与 T2D 相关 拟议的项目将是第一个系统地检查 T2D 易感性遗传基础的项目 与 iAs 暴露有关。该项目生成的数据可以建议新的风险评估和 在普遍接触 iAs 且采取补救措施的人群中采取预防策略 减少人类接触无机砷失败

PROJECT SUMMARY Inorganic arsenic (iAs) is a common drinking water and food contaminant poisoning hundreds of millions of individuals around the world, including the US. It has been established that chronic exposure to iAs is associated with risk of type 2 diabetes (T2D) and that metabolism of iAs into its methylated forms is a critical component in determining T2D risk in humans. The methylation of iAs is catalyzed by arsenic methyltransferase (AS3MT). While studies using genome-wide approaches have identified polymorphisms in AS3MT as the major genetic factor determining the inter-individual differences in iAs metabolism, the genetic underpinning of the susceptibility to iAs-associated T2D has never been systematically examined, leaving a critical knowledge gap. Results of population studies carried out by our team suggest that polymorphisms in AS3MT and in several other genes involved in iAs metabolism or in the regulation of glucose homeostasis may also contribute to T2D risk. This project will use the Diversity Outbred (DO) and Collaborative Cross (CC) mouse populations to address this knowledge gap. The central hypothesis of this proposal is that multiple genes and haplotypes (in addition to As3mt) will be tied to diabetic phenotypes associated with iAs exposure. We will first examine the range of metabolic phenotypes in a large cohort of DO mice exposed to iAs. Differences in iAs metabolism will be assessed in both urine and liver. Mice will be genotyped and genetic mapping will lead to identification of Quantitative Trait Loci (QTLs) and founder haplotypes associated with risk and protective alleles. The roles of sex, iAs exposure dose and gene expression as a mediator of haplotype- phenotype relationships will then be established using CC strains with contrasting alleles at the QTLs. Finally, we will assess the roles of the risk loci identified in the mouse cohorts in the inter-individual differences in iAs metabolism and metabolic phenotypes in an existing human cohort in which iAs exposure was linked to T2D The proposed project will be the first to systematically examine genetic foundation of the susceptibility to T2D associated with iAs exposure. Data generated by this project could suggest new risk assessment and prevention strategies in populations where iAs exposures are common and where remediation efforts aiming to reduce human exposure to iAs failed