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

基本信息

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
项目类别：
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

项目摘要

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.

非酒精性脂肪性肝病（NAFLD）导致的肝细胞癌（HCC）负担增加过去二十年里的大幅增长。尽管 NAFLD 和 HCC 对拉丁裔的影响不成比例个人中，很少有拉丁美洲人参与评估 HCC 风险的遗传和流行病学研究。先前遗传研究确实包括拉丁裔的 NAFLD 风险，但由于使用候选基因方法而受到限制无法检测新的遗传关联。其他研究仅限于来自一个国家的个人，因此无法考虑拉丁裔之间令人难以置信的多样性如何导致遗传风险或差异 NAFLD 表型、肝硬化风险或 HCC 风险。在拟议的研究中，博士。琼斯和弗洛雷斯会工作作为多个主要研究者进行合作。他们将与联合研究人员一起与其他研究人员合作肝硬化网络 (LCN) 成员开发精确、个性化的 NAFLD 治疗方法专门针对拉丁裔这一弱势群体的预测和 HCC 风险分层疾病负担。在目标 1 中，博士。弗洛雷斯和琼斯将利用两项研究的现有数据（加州大学洛杉矶分校 ATLAS 社区健康倡议和 NIH 所有人研究计划）开展全基因组关联研究（GWAS），全表型关联研究，并为 NAFLD 患者创建多基因风险评分。我们所有人 ATLAS 旨在招募多元化的参与者，以确保精准医学的包容性和普遍性研究。因此，拟议的研究代表了 NAFLD 中规模最大、种族最多样化的 GWAS，涉及 21,199 名已确定患有 NAFLD 的个体。我们将定义已知单曲和新颖单曲之间的关系核苷酸多态性 (SNP) 和 NAFLD、NASH、NAFLD-肝硬化和 NAFLD-HCC 的风险，按种族、原籍地区和遗传血统。与 LCN 研究人员合作，博士。弗洛雷斯和琼斯将将患有 NAFLD 的拉丁裔参与者纳入一项前瞻性病例对照研究，旨在描述基因特征已知和新的遗传 NAFLD 相关 SNP 与环境风险之间的环境相互作用因素包括艾滋病毒、糖尿病和代谢综合征。他们将吸引新的和现有的 LCN 队列参与者以及迈阿密大学 (UM)、迈阿密大学现有队列中注册的参与者加州洛杉矶大学 (UCLA) 和波多黎各大学综合癌症中心 (UPRCCC)。全部站点将识别并招募患有 NAFLD 和健康对照的新病例。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 患者肝硬化的影响，(2) NAFLD 肝硬化患者的肝代偿失调，以及 (3) HCC 患有或不患有肝硬化的 NAFLD 患者的风险。 NAFLD 是美国增长最快的肝硬化病因对拉丁裔的影响尤为严重，他们的 HCC 负担也最高。通过识别最强的风险在大量不同的人群中，导致 NAFLD 表型、肝硬化失代偿和 HCC 风险差异的因素对于拉丁裔样本，我们可以识别那些风险最大的人，并对可改变的风险因素进行干预。