This career development and research proposal is designed to provide me with specialized training and mentored guidance that will help me become an independent cancer investigator. The overall aim of my research project is to investigate the role of genetic influence on the development of liver disease/cancer in a sample of Mexican adults, an understudied, at-risk population. This research project will provide an ideal opportunity to apply the specialized knowledge and skills in genetic and molecular epidemiology that I will obtain as part of my proposed career development activities. Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are earlier forms of liver disease that can progress to liver cancer. The prevalence of NAFLD, NASH and liver cancer is highest among Latinos, followed by Caucasians and African Americans. Known risk factors for NAFLD and NASH include obesity, metabolic syndrome, diabetes mellitus, and insulin resistance. Although the environmental risk factors for NAFLD and NASH are well established, the genetic basis of hepatic steatosis is largely unknown. Even less is known about the genetic factors that contribute to liver disease/cancer susceptibility among Latinos, despite the disproportionate burden of Liver and intrahepatic bile ducts among this group. The main goal of this research project is to explore how genetic susceptibility may interact with known risk factors (e.g. obesity metabolic syndrome, and diabetes) to increase risk of NAFLD and NASH among Mexican adults. A nested case-control study will be conducted using a sample of 480 cases (180 NAFLD and 300 NASH, all clinically confirmed) and 480 healthy controls from central Mexico. The existing clinical, genetic, and questionnaire data obtained in 2011-2013 as part of the Mexican Health Worker Cohort Study (MHWCS) and from a bariatric clinic in Mexico City will be integrated. The main hypothesis of this research is that the effect of obesity, metabolic syndrome, and diabetes on increased risk of NAFLD and NASH will be greater in the presence of high-risk single-nucleotide polymorphism (SNPs) such as PNPLA3 (rs738409). A better understanding of the mechanisms underlying the genetic and environmental factors that are associated with an increased risk of NAFLD and NASH may help to reduce liver cancer disparities among Latinos. The results of this study could also provide new targets for prophylactic and therapeutic interventions. Since Mexican-Americans are at increased risk of liver disease/cancer it is particularly important to investigate the mechanisms through which genes influence disease progression in this population. By finding better ways to identify and treat NAFLD and NASH at the earlier stages of liver disease we can help prevent future cases of Liver and intrahepatic bile ducts. PUBLIC HEALTH RELEVANCE: Relatively little is known about the genetic factors that contribute to liver disease/cancer susceptibility among Mexican-Americans and other Latino populations, despite the disproportionate burden of Liver and intrahepatic bile ducts among this group. This research project will examine the complex interplay between genetic and environmental factors, and risk of liver disease in a sample of Mexican adults. An improved understanding of the mechanisms through which genes influence liver disease progression may help prevent future cases of liver cancer