Genetic and Environmental Risk of Liver Disease/Cancer among Mexicans

 描述(由申请人提供)：这份职业发展和研究提案旨在为我提供专门的培训和指导，帮助我成为一名独立的癌症研究员。我的研究项目的总体目标是在墨西哥成年人的样本中调查遗传影响在肝病/癌症发展中的作用，墨西哥成年人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来应用遗传和分子流行病学方面的专门知识和技能，这些知识和技能将作为我拟议的职业发展活动的一部分而获得。非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)是可发展为肝癌的早期形式的肝病。拉丁美洲人中NAFLD、NASH和肝癌的患病率最高，其次是高加索人和非裔美国人。NAFLD和NASH的已知危险因素包括肥胖、代谢综合征、糖尿病和胰岛素抵抗。尽管NAFLD和NASH的环境危险因素已经确定，但肝脏脂肪变性的遗传基础很大程度上是未知的。尽管拉美裔人群中患肝癌的负担不成比例，但人们对导致拉美裔人群肝脏疾病/癌症易感性的遗传因素了解更少。这项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(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患NAFLD和NASH的风险。将对来自墨西哥中部的480例病例(180例非酒精性脂肪肝和300例非酒精性脂肪肝)和480例健康对照进行嵌套病例对照研究。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一家减肥诊所获得的现有临床、遗传和问卷数据将被整合。这项研究的主要假设是，在存在PNPLA3(Rs738409)等高危单核苷酸多态性(SNPs)的情况下，肥胖、代谢综合征和糖尿病对NAFLD和NASH风险增加的影响将更大。更好地了解与NAFLD和NASH风险增加相关的遗传和环境因素的潜在机制，可能有助于减少拉丁美洲人之间的肝癌差异。本研究结果还可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，因此研究基因影响这一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.