Genetic underpinning of diabetes associated with arsenic exposure

项目总结 无机砷(IAS)是一种常见的饮用水和食物污染物，可毒害数亿人 世界各地的个人，包括美国。已经确定，长期暴露于IAS是 与2型糖尿病(T2D)风险相关，IAS向其甲基化形式的代谢是至关重要的 在确定人类T2D风险方面具有重要作用。IAS的甲基化是由砷催化的 甲基转移酶(AS3MT)。虽然使用全基因组方法的研究已经确定了在 AS3MT是决定IAS代谢个体间差异的主要遗传因素，遗传 对IAS相关的T2D易感性的基础从未进行过系统的研究，留下了一个 关键的知识鸿沟。我们团队进行的人群研究结果表明，在 AS3MT和其他几个参与IAS代谢或调节葡萄糖稳态的基因可能 也会导致T2D风险。该项目将使用多样性远缘杂交(DO)和合作杂交(CC) 解决这一知识鸿沟的老鼠种群。这一提议的中心假设是 基因和单倍型(除AS3MT外)将与IAS相关的糖尿病表型相关 曝光。我们将首先检查暴露在一大群DO小鼠中的代谢表型范围 国际会计准则。将在尿液和肝脏中评估IAS代谢的差异。小鼠将进行基因分型和遗传 作图将导致识别与风险相关的数量性状基因座(QTL)和创始人单倍型 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调节因子的作用 然后将利用在QTL上具有对比等位基因的CC菌株来建立表型关系。最后， 我们将评估在小鼠队列中确定的风险基因在IAS的个体间差异中的作用 IAS暴露与T2D相关的现有人群中的代谢和代谢表型 拟议的项目将是第一个系统地研究t2d易感性的遗传基础的项目。 与IAS暴露有关。该项目产生的数据可能会建议进行新的风险评估和 在IAS暴露很常见的人群中的预防战略，以及旨在开展补救工作的人群 减少人类对IAS的暴露失败

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