It is well known that the causes of common multifactorial diseases are both genetic and environmental in origin. Epidemiological studies (including the investigators? own international investigations) have shown that consuming drinking water with high levels of inorganic arsenic results in high health risk. A current challenge is to identify genetic polymorphisms in a set of environmentally-associated genes that may independently confer modest risk, but collectively comprise high risk profiles that predispose an individual to poor health consequences from arsenic exposure. The primary objective of this planning grant is to form a consortium with the capability to meet this current challenge. To accomplish this objective, this project has 3 specific aims. The first specific aim is to organize a cohesive group of multidisciplinary researchers with a shared mutual understanding of the methodologies, issues and problems involved in carrying out molecular epidemiology studies. The proposed consortium has researchers from 4 institutions: University of California San Francisco, University of California Berkeley (UC Berkeley), Children?s Hospital Oakland Research Institute and National Cancer Institute (NCI), NIH. The second specific aim is to create and perform a series of pilot studies designed to investigate concepts, hypotheses and technologies relevant to molecular epidemiology of arsenic-exposed populations. Three such studies are included in this application: (1) to determine the most feasible high output DNA SNP technology for investigating genotypic differences between individuals, (2) to identify the most appropriate set of specific genes and SNPs for investigations of arsenic-exposed populations, and (3) to develop appropriate methodologies for discriminating and prioritizing the results of the multiple statistical testing involved in epidemiology studies using SNP genotyping. After completion of these pilot projects, the third specific aim is to prepare and submit to NIH a detailed proposal to perform a molecular epidemiology study to systematically investigate genetic factors that influence susceptibility to arsenic-induced skin lesions in a population in India. About 400 blood samples for this population have already been collected and are held in frozen storage. As a result of this systematic study, individuals at particular risk for arsenic-induced effects will be identified and subject to intensified surveillance screening. In addition, mechanistic information will provide potential targets for preventive and curative interventions in exposed populations (e.g., nutrients or drugs).
