Genetic and Environmental Risk of Liver Disease/Cancer among Mexicans

墨西哥人肝病/癌症的遗传和环境风险

• 批准号: 9322446
• 负责人: Yvonne Nicole Flores
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322446
• 关键词: Adult; African American; Alcoholic Liver Diseases; Alleles; Apolipoproteins B; Bariatrics; CETP gene; CSPG3 gene; CYP2E1 gene; Candidate Disease Gene; Carcinoma; Cirrhosis; Cities; Clinic; Clinical; Cohort Studies; Complex; Data; Development; Diabetes Mellitus; Disease Progression; Environmental Risk Factor; Ethnic Origin; Fatty Liver; Frequencies; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Goals; Grant; Health; Hepatitis B; Hepatitis C; Hispanics; IL6 gene; Incidence; Indigenous; Infection; Inflammation; Insulin Resistance; Insulin Resistance Pathway; Knowledge; Latino; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Medical Genetics; Mentors; Metabolic syndrome; Mexican; Mexican Americans; Mexico; Modification; Molecular Epidemiology; Nested Case-Control Study; Not Hispanic or Latino; Obesity; Oxidative Stress; PPARG gene; Population; Populations at Risk; Predisposition; Prevalence; Questionnaires; Race; Research; Research Personnel; Research Project Grants; Research Proposals; Risk; Risk Factors; Role; SLC2A1 gene; STAT3 gene; STAT4 gene; Sampling; Single Nucleotide Polymorphism; Steatohepatitis; TNF gene; Therapeutic Intervention; Time; Training; cancer health disparity; career development; caucasian American; design; gene interaction; genetic epidemiology; genetic risk factor; high risk; improved; lipid metabolism; liver development; non-alcoholic fatty liver; nonalcoholic steatohepatitis; prevent; prophylactic; public health relevance; skills

 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.

 描述（由申请人提供）：该职业发展和研究计划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者。我的研究项目的总体目标是调查遗传影响的作用。墨西哥成年人样本中肝病/癌症的发展，这是一个未被充分研究的高危人群，该研究项目将为应用我将获得的专业知识以及遗传技能和分子流行病学知识提供一个理想的机会。拟议的职业发展非酒精性脂肪性肝病 (NAFLD) 和非酒精性脂肪性肝炎 (NASH) 是可进展为肝癌的早期肝脏疾病。 NAFLD、NASH 和肝癌的患病率在拉丁裔中最高，其次是白人和白人。非裔美国人。已知的 NAFLD 和 NASH 风险因素包括肥胖、代谢综合征、糖尿病和胰岛素抵抗。尽管 NAFLD 和 NASH 的环境风险因素已明确，但遗传因素仍然存在。尽管拉丁美洲人患肝癌的负担不成比例，但对导致肝病/癌症易感性的遗传因素知之甚少。该研究项目的主要目标是探索遗传因素。易感性可能与已知的危险因素（例如肥胖代谢综合征和糖尿病）相互作用，从而增加墨西哥成年人患 NAFLD 和 NASH 的风险，将使用 480 例样本进行巢式病例对照研究。 （180 名 NAFLD 和 300 名 NASH，均经过临床证实）和来自墨西哥中部的 480 名健康对照者 2011-2013 年作为墨西哥卫生工作者队列研究 (MHWCS) 的一部分从一家减肥诊所获得的现有临床、遗传和问卷数据。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 风险增加的影响会更大。高风险单核苷酸多态性 (SNP)，例如 PNPLA3 (rs738409)，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。这项研究的结果还可以为预防和治疗干预提供新的目标，因为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。