Biological mechanisms underlying inherited genetic effects on arsenic metabolism

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PROJECT SUMMARY/ABSTRACT Over 100 million people in over 70 countries consume water that is contaminated with inorganic arsenic (iAs), a toxicant that has been linked to health risks that include cancer, cardiovascular disease, and impaired cognitive development. Susceptibility to iAs toxicity is partially determined by genetic factors that influence an individual’s ability to metabolize iAs, a process that facilitates the removal of arsenic from the body (in urine). A major focus of epidemiological research on iAs exposure has been identifying inherited genetic variation that influences arsenic metabolism efficiency (AME) in order to (1) enable classification of individuals based on toxicity risk and (2) elucidate the biological mechanism underlying inter-individual differences in AME to inform the development of interventions that reduce toxicity risk. While prior studies have successfully identified genetic variants associated with AME and toxicity risk, their biological mechanisms are not fully understood. The long-term goal of this project is to utilize emerging and innovative gene-editing approaches to functionally elucidate the mechanisms by which SNPs impact cellular arsenic metabolism in humans. The objective of this proposal is to functionally define the causal FTCD and AS3MT SNPs that we have previously established as strongly associated with AME in human populations exposed to arsenic. Our central hypotheses are (1) the minor allele at FTCD SNP rs61735836 modifies enzymatic activity thus reducing arsenic methylation and (2) the causal AS3MT SNP(s) reduce AS3MT RNA and protein expression, also leading to reduced arsenic methylation. Completion of these studies will define a mechanistic framework for the investigation of additional SNPs related to arsenic metabolism. Identifying causal variants that affect AME and understanding their mechanisms will be broadly relevant to the many diseases for which arsenic exposure impacts risk, because these SNPs likely impact internal dose of arsenic.