Thursday, May 26, 2022
5/26/2022
SUMMARY Inorganic arsenic (iAs) is a human carcinogen, and exposure to iAs affects >200 million individuals worldwide. In Bangladesh, >57 million individuals (>25% of exposed individuals worldwide) are chronically exposed to iAs through drinking-water from naturally contaminated wells that have some of the highest iAs concentrations reported in the world. 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 toxicity risk. Identifying genetic determinants of AME to help identify individuals at higher risk for toxicity has been a focus within genetic epidemiology research. Previous studies have identified genetic variants in the AS3MT (10q24.32) and FTCD (21q22.3) regions as showing clear association with AME. However, we currently know of no other regions of the human genome that contain variants that show robust and replicable evidence of association with AME, although studies of heritability suggest that additional variants are likely to exist. Our first aim is to identify new regions that contain inherited genetic variation that affects individuals’ ability to metabolize arsenic and their susceptibility to toxicity. We will achieve this aim by leveraging existing data from >7,000 Bangladeshi 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). Our second aim is to assess the impact of returning personal genetic information on susceptibility to arsenic toxicity to participants in rural Bangladesh. Using existing participant data on inherited genetic variation known to impact AME and risk for arsenic toxicities, we will examine the impact of returning of genetic information on arsenic susceptibility on subsequent behavioral changes related to arsenic exposure reduction within HEALS. Returning genetic results to research participants is timely as we are now aware of specific genetic risk factors that have a clear impact on arsenic toxicity risk. The proposed work will make significant contributions to knowledge of genetic and environmental susceptibility to cancer and will inform potential prevention strategies. We hope to identify novel inherited variants that impact susceptibility to arsenic exposure. We will test the feasibility and benefits of returning genetic results to participants in a rural, low resource setting, an intervention that, if successful, could be expanded in this population to reduce exposure and prevent cancer. The training activities described in this proposal will build critical expertise in genetic epidemiology, environmental health, and intervention research, and prepare the trainee for a career focused on generating knowledge of genetic and environmental risk factors and applying genetic technologies to improve health and reduce exposure in at-risk and understudied populations.
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