Abstract 1440: Identifying inherited genetic variation that impacts individuals’ ability to metabolize arsenic and susceptibility to toxicity

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Abstract Inorganic arsenic (iAs) is a class I human carcinogen, and exposure to iAs affects >200 million individuals worldwide. In Bangladesh, >57 million individuals are chronically exposed to iAs through drinking-water. There is inter-individual variation in arsenic metabolism efficiency (AME) due to inherited genetic variation, and this variability impacts individuals’ internal dose of arsenic and their susceptibility to toxicity. Identifying genetic determinants of AME to help identify individuals at higher risk for toxicity has been a focus within genetic epidemiology research. Consumed arsenic enters the blood in as iAs. Sequential reduction and methylation reactions are catalyzed by glutathione and arsenic methyltransferase (AS3MT) respectively, producing monomethylated (MMA) and dimethylated (DMA) forms of arsenic. Generation of DMA is beneficial because DMA is more easily expelled from the body in urine compared to MMA or iAs. AME is often represented by the percent of the arsenic species in urine that exists as DMA. Previous studies have identified genetic variants in the AS3MT (10q24.32) and FTCD (21q22.3) regions as showing clear association with AME. However, additional regions containing variants showing robust and replicable association with AME have not yet been identified, although studies of AME heritability suggest that additional variants are likely to exist. We used data from >7,000 participants from two studies of Bangladesh individuals with varying levels of exposure to arsenic through drinking water (The Health Effects of Arsenic Longitudinal Study, HEALS, and the Bangladesh Vitamin E and Selenium Trial, BEST) to identify genetic variation that impacts individuals’ ability to metabolize arsenic and their susceptibility to toxicity (i.e., arsenic-induced skin lesions). Our preliminary results suggest novel associations with AME in the 1q24.3 region (p= 5.16 x10-14) and with skin lesion risk in the 6p21.33 region (p=1.37x10-9). The identified variants in the 1q24.3 region reside in and around the FMO3 gene. FMOs are enzymes involved in xenobiotic metabolism; therefore, it is plausible that they may play a role in arsenic metabolism. The 6p21.33 signal is in the major histocompatibility complex (MHC) region, which contains numerous key immune response genes (e.g., HLA genes). These results suggest the existence of additional variants associated with AME and arsenic toxicity risk. Citation Format: Lizeth I. Tamayo, Lin Tong, Muhammad G. Kibriya, Farzana Jasmine, Habibul Ahsan, Brandon L. Pierce. Identifying inherited genetic variation that impacts individuals’ ability to metabolize arsenic and susceptibility to toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1440.