Genetic and Environmental risk of NAFLD-related HCC In All Latinos: the GENIAL Study

所有拉丁美洲人 NAFLD 相关 HCC 的遗传和环境风险：GENIAL 研究

• 批准号: 10856113
• 负责人: Yvonne Nicole Flores
• 金额: $ 34.1万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10856113
• 关键词: Affect; Aflatoxins; Alanine Transaminase; All of Us Research Program; Behavioral; Biological Markers; Black race; California; Candidate Disease Gene; Case/Control Studies; Characteristics; Chronic Hepatitis B; Cicatrix; Cirrhosis; Clinical; Collaborations; Community Health; Comprehensive Cancer Center; Country; Data; Detection; Diabetes Mellitus; Diet; Disparate; Disparity; Enrollment; Ensure; Environmental Risk Factor; Epidemiology; Ethnic Population; Fatty Liver; Genetic; Genetic Polymorphism; Genetic Risk; Genetic study; Goals; HIV; Hepatic; Hepatitis C; Incidence; Indigenous American; Individual; Institution; Insulin Resistance; Latino; Latino Population; Lead; Liver; Liver Cirrhosis; Liver Fibrosis; Los Angeles; Malignant Neoplasms; Malignant neoplasm of liver; Medical; Metabolic syndrome; Mexico; Neighborhoods; Nucleotides; Obesity Epidemic; Participant; Patient Recruitments; Patients; Persons; Poverty; Prevalence; Primary carcinoma of the liver cells; Principal Investigator; Progressive Disease; Prospective cohort; Puerto Rico; Race; Research; Research Personnel; Resources; Risk; Risk Factors; Risk Reduction; STAT4 gene; Sampling; Severities; Single Nucleotide Polymorphism; Site; Steatohepatitis; United States; United States National Institutes of Health; Universities; Vulnerable Populations; Work; burden of illness; clinical risk; cohort; disease phenotype; disease prognosis; disorder risk; epidemiology study; gene environment interaction; genetic association; genome wide association study; high risk; improved; liver transplantation; member; modifiable risk; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; participant enrollment; personalized approach; personalized medicine; personalized screening; phenome; polygenic risk score; population based; precision medicine; prospective; racial diversity; racial population; recruit; risk prediction model; risk stratification; screening program; simple steatosis; social; social culture; treatment strategy

The burden of hepatocellular carcinoma (HCC) due to non-alcoholic fatty liver disease (NAFLD) has increased substantially over the past two decades. Although both NAFLD and HCC disproportionately affect Latino individuals, few Latinos were included in genetic and epidemiologic studies evaluating HCC risk. Prior genetic studies examining NAFLD risk that did include Latinos were limited in that they used candidate-gene approaches which cannot detect novel genetic associations. Other studies limited inclusion to individuals from one country, and thus could not consider how the incredible diversity among Latinos might drive genetic risk or differences in NAFLD phenotype, risk of cirrhosis, or HCC risk. In the proposed study, Drs. Jones and Flores will work collaboratively as multiple principal investigators. Along with co-investigators, they will collaborate with other members of the Liver Cirrhosis Network (LCN) to develop precise, personalized approaches to NAFLD prognostication and HCC risk stratification targeted specifically to Latinos, a vulnerable population with excess disease burden. In Aim 1, Drs. Flores and Jones will leverage existing data from two studies (UCLA ATLAS Community Health Initiative and NIH All of Us Research Program) to conduct a genome wide association study (GWAS), phenome-wide association study, and create polygenic risk scores in persons with NAFLD. All of Us and ATLAS aim to enroll diverse participants to ensure inclusivity and generalizability in Precision Medicine research. As such, the proposed study represents the largest, most racially diverse GWAS in NAFLD with 21,199 individuals with NAFLD already identified. We will define the relationship between known and novel single nucleotide polypmorphisms (SNPs) and risk of NAFLD, NASH, NAFLD-cirrhosis, and NAFLD-HCC, stratified by race, region of origin and genetic ancestry. In collaboration with LCN investigators, Drs. Flores and Jones will enroll Latino participants with NAFLD into a prospective case-control study that aims to characterize gene- environment interactions between known and novel genetic NAFLD-associated SNPs and environmental risk factors including HIV, diabetes, and metabolic syndrome. They will engage new and existing LCN Cohort participants as well as participants enrolled in existing cohorts at the University of Miami (UM), the University of Los Angeles California (UCLA) and the University of Puerto Rico Comprehensive Cancer Center (UPRCCC). All sites will identify and recruit new cases with NAFLD and healthy controls. We will develop polygenic risk scores that incorporate genetic, clinical, sociocultural, behavioral, and environmental characteristics to predict (1) risk of cirrhosis in persons with NAFLD, (2) hepatic decompensation in NAFLD patients with cirrhosis, and (3) HCC risk in NAFLD patients with or without cirrhosis. NAFLD is the fastest growing cause of cirrhosis in the US and disproportionately impacts Latinos who also have the highest HCC burden. By identifying the strongest risk factors that drive differences in NAFLD phenotype, cirrhosis decompensation, and HCC risk in a large, diverse Latino sample, we can identify those at greatest risk and intervene on modifiable risk factors.

由于非酒精性脂肪性肝病（NAFLD）导致的肝细胞癌（HCC）负担增加 在过去的二十年里，虽然NAFLD和HCC都不成比例地影响拉丁美洲人， 个体，很少有拉丁美洲人被纳入评估HCC风险的遗传学和流行病学研究。先前遗传 包括拉丁美洲人在内的NAFLD风险研究受到限制，因为他们使用了候选基因方法 它不能检测新的遗传关联。其他研究仅限于来自一个国家的个人， 因此无法考虑拉丁美洲人令人难以置信的多样性如何可能导致遗传风险或 NAFLD表型、肝硬化风险或HCC风险。在这项研究中，琼斯博士和弗洛雷斯将 作为多个主要研究者进行合作。沿着共同研究者，他们将与其他 肝硬化网络（LCN）的成员开发精确的，个性化的NAFLD方法 专门针对拉丁美洲人的分层和HCC风险分层，这是一个具有过度 疾病负担。在目标1中，弗洛雷斯博士和琼斯博士将利用两项研究（UCLA ATLAS）的现有数据 社区健康倡议和NIH所有人研究计划）进行全基因组关联研究 （GWAS），全表型关联研究，并在NAFLD患者中创建多基因风险评分。我们所有人 和ATLAS旨在招募不同的参与者，以确保精准医学的包容性和普遍性 research.因此，拟议的研究代表了NAFLD中最大，最具种族多样性的GWAS， 已经确定的NAFLD患者。我们将定义已知和新颖的单之间的关系 核苷酸多态性（SNP）与NAFLD、NASH、NAFLD-肝硬化和NAFLD-HCC的风险，按 种族、原产地和遗传祖先。弗洛雷斯博士和琼斯博士将与LCN的调查人员合作， 将患有NAFLD的拉丁裔参与者纳入一项前瞻性病例对照研究，该研究旨在描述基因特征， 已知和新的NAFLD相关SNPs与环境风险之间的相互作用 艾滋病、糖尿病和代谢综合征等因素。他们将招募新的和现有的LCN队列 参与者以及参与者在迈阿密大学（UM）， 洛杉矶加州（UCLA）和波多黎各大学综合癌症中心（UPRCCC）。所有 研究中心将识别并招募新的NAFLD病例和健康对照。我们将开发多基因风险评分 结合遗传、临床、社会文化、行为和环境特征来预测（1）风险 NAFLD患者肝硬化的发生率，（2）NAFLD伴肝硬化患者的肝失代偿，以及（3）HCC 有或无肝硬化的NAFLD患者的风险。NAFLD是美国增长最快的肝硬化原因， 不成比例地影响拉丁美洲人，他们也有最高的HCC负担。通过识别最大的风险 在一个大的、多样化的研究中， 拉丁裔样本，我们可以确定那些风险最大的人，并对可改变的风险因素进行干预。