Genetic and Environmental Risk of Liver Disease/Cancer among Mexicans

 描述（由申请人提供）：这个职业发展和研究计划旨在为我提供专业培训和指导，帮助我成为一名独立的癌症研究者。我的研究项目的总体目标是调查遗传影响对墨西哥成年人样本中肝脏疾病/癌症发展的作用，这是一个研究不足的高危人群。这个研究项目将提供一个理想的机会，应用遗传和分子流行病学的专业知识和技能，我将获得作为我拟议的职业发展活动的一部分。非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）是肝脏疾病的早期形式，可进展为肝癌。NAFLD，NASH和肝癌的患病率在拉丁美洲人中最高，其次是高加索人和非洲裔美国人。NAFLD和NASH的已知风险因素包括肥胖、代谢综合征、糖尿病和胰岛素抵抗。虽然NAFLD和NASH的环境风险因素已经得到了很好的确定，但肝脏脂肪变性的遗传基础在很大程度上是未知的。对拉丁美洲人中导致肝病/癌症易感性的遗传因素知之甚少，尽管这一群体中肝癌的负担不成比例。该研究项目的主要目标是探索遗传易感性如何与已知的风险因素（例如肥胖代谢综合征和糖尿病）相互作用，以增加墨西哥成年人NAFLD和NASH的风险。将使用来自墨西哥中部的480例病例（180例NAFLD和300例NASH，均经临床证实）和480例健康对照样本进行巢式病例对照研究。将整合2011-2013年作为墨西哥卫生工作者队列研究（MHWCS）的一部分以及从墨西哥城肥胖症诊所获得的现有临床、遗传和问卷调查数据。这项研究的主要假设是，肥胖、代谢综合征和糖尿病对NAFLD和NASH风险增加的影响在存在高风险单核苷酸多态性（SNP）如PNPLA 3（rs738409）的情况下会更大。更好地了解与NAFLD和NASH风险增加相关的遗传和环境因素的机制可能有助于减少拉丁美洲人之间的肝癌差异。这项研究的结果也可以为预防和治疗干预提供新的靶点。由于墨西哥裔美国人患肝病/癌症的风险增加，因此研究基因影响该人群疾病进展的机制尤为重要。通过找到更好的方法在肝病的早期阶段识别和治疗NAFLD和NASH，我们可以帮助预防未来的肝癌病例。

 DESCRIPTION (provided by applicant): 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 cancer 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 cancer.