Genetic underpinning of diabetes associated with arsenic exposure

PROJECT SUMMARYInorganic arsenic (iAs) is a common drinking water and food contaminant poisoning hundreds of millions ofindividuals around the world, including the US. It has been established that chronic exposure to iAs isassociated with risk of type 2 diabetes (T2D) and that metabolism of iAs into its methylated forms is a criticalcomponent in determining T2D risk in humans. The methylation of iAs is catalyzed by arsenicmethyltransferase (AS3MT). While studies using genome-wide approaches have identified polymorphisms inAS3MT as the major genetic factor determining the inter-individual differences in iAs metabolism, the geneticunderpinning of the susceptibility to iAs-associated T2D has never been systematically examined, leaving acritical knowledge gap. Results of population studies carried out by our team suggest that polymorphisms inAS3MT and in several other genes involved in iAs metabolism or in the regulation of glucose homeostasis mayalso 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 multiplegenes and haplotypes (in addition to As3mt) will be tied to diabetic phenotypes associated with iAsexposure. We will first examine the range of metabolic phenotypes in a large cohort of DO mice exposed toiAs. Differences in iAs metabolism will be assessed in both urine and liver. Mice will be genotyped and geneticmapping will lead to identification of Quantitative Trait Loci (QTLs) and founder haplotypes associated with riskand 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 iAsmetabolism and metabolic phenotypes in an existing human cohort in which iAs exposure was linked to T2DThe proposed project will be the first to systematically examine genetic foundation of the susceptibility to T2Dassociated with iAs exposure. Data generated by this project could suggest new risk assessment andprevention strategies in populations where iAs exposures are common and where remediation efforts aiming toreduce human exposure to iAs failed