Genetic underpinning of diabetes associated with arsenic exposure

与砷暴露相关的糖尿病的遗传基础

• 批准号: 10561667
• 负责人: Rebecca Fry
• 金额: $ 64.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561667
• 关键词: Address; Alleles; Arsenic; Automobile Driving; Chromosome Mapping; Chronic; Data; Development; Diabetes Mellitus; Disease; Dose; Exposure to; Food; Foundations; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Haplotypes; Health; Homeostasis; Human; Individual; Individual Differences; Insulin; Knowledge; Link; Liver; Maps; Mediator; Metabolism; Methylation; Methyltransferase; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Peripheral; Phenotype; Poison; Poisoning; Population; Population Heterogeneity; Population Study; Predisposition; Prevention strategy; Process; Publishing; Quantitative Trait Loci; Research; Resources; Risk; Risk Assessment; Role; Signal Transduction; Structure of beta Cell of islet; Testing; Tissue-Specific Gene Expression; Tissues; Toxic effect; Translating; Urine; blood glucose regulation; cohort; diabetes risk; diabetic; diabetogenic; disease registry; drinking water; exceptional responders; exposed human population; genetic variant; genome-wide; glucose metabolism; inhibitor; insulin secretion; insulin signaling; metabolic phenotype; novel; oxidation; protective allele; remediation; risk variant; sex; tool; translational approach

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

项目摘要 无机砷（IAS）是一种常见的饮用水和食物，污染了数亿美元 包括美国在内的世界各地的个人。已经确定长期暴露于IAS 与2型糖尿病风险（T2D）以及IAS代谢成甲基化形式相关的是关键 确定人类T2D风险的组成部分。 IAS的甲基化被砷催化 甲基转移酶（AS3MT）。虽然使用全基因组方法的研究确定了多态性 AS3MT是确定IAS代谢的个体间差异的主要遗传因素，遗传 从未对IAS相关T2D的易感性的基础进行系统检查，从而使 批判知识差距。我们团队进行的人口研究结果表明，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 也有助于T2D风险。该项目将使用多样性（DO）和协作十字架（CC） 鼠标群体以解决此知识差距。该提议的核心假设是多个 基因和单倍型（除了AS3MT之外）将与与IAS相关的糖尿病表型绑定 接触。我们将首先检查大型DO小鼠队列中的代谢表型范围 IAS。 IAS代谢的差异将在尿液和肝脏中评估。小鼠将是基因型和遗传的 映射将导致识别定量性状基因座（QTL）和与风险相关的创始人单倍型 和保护性等位基因。性别，IAS暴露剂量和基因表达的作用是单倍型的介体 然后，将使用与QTL的对比等位基因的CC菌株建立表型关系。最后， 我们将评估小鼠队列中鉴定出的风险基因座在IAS间个体差异中的作用 在现有的人类队列中，IAS暴露与T2D有关的代谢和代谢表型 拟议的项目将是第一个系统地检查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建议新的风险评估和 IAS暴露是普遍的，以及旨在的补救工作的人群中的预防策略 减少人类对IAS的接触失败