Genetic underpinning of diabetes associated with arsenic exposure

项目摘要 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， 世界各地的人，包括美国。已经确定，长期暴露于iAs 与2型糖尿病（T2 D）的风险相关，iAs代谢为甲基化形式是关键的 确定人类T2 D风险的一部分。砷催化甲基化反应 甲基转移酶（AS 3 MT）。虽然使用全基因组方法的研究已经确定了 AS 3 MT是决定iAs代谢个体间差异的主要遗传因素， 对iAs相关T2 D易感性的基础从未被系统地研究过， 关键的知识差距。我们小组进行的人群研究结果表明， AS 3 MT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T2 D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缺口。这一建议的核心假设是， 基因和单倍型（除As 3 mt外）将与iAs相关的糖尿病表型相关 exposure.我们将首先检查暴露于以下物质的DO小鼠的大队列中的代谢表型的范围： 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 作图将导致与风险相关的数量性状基因座（QTL）和创始单倍型的鉴定 和保护性等位基因。性别、iAs暴露剂量和基因表达作为单倍型介导因子的作用- 然后使用在QTL处具有对比等位基因的CC菌株建立表型关系。最后， 我们将评估在小鼠队列中确定的风险基因座在iAs个体间差异中的作用， iAs暴露与T2 D相关的现有人类队列中的代谢和代谢表型 该项目将首次系统地研究T2 D易感性的遗传基础。 与iAs暴露有关。该项目产生的数据可能会提出新的风险评估， iAs暴露常见的人群中的预防策略，以及补救措施旨在 减少人体接触iAs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