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.

由于非酒精性脂肪肝疾病（NAFLD）引起的肝细胞癌（HCC）的负担增加了在过去的二十年中，基本上是基本的。尽管NAFLD和HCC都会不成比例地影响拉丁裔个体，在评估HCC风险的遗传和流行病学研究中很少有拉丁美洲人。先前的遗传研究nafld风险的研究确实有限，因为他们使用了候选基因方法无法检测新的遗传关联。其他研究将包容性限制在一个国家的个人中，因此，无法考虑拉丁美洲人之间令人难以置信的多样性如何驱动遗传风险或差异 NAFLD表型，肝硬化的风险或HCC风险。在拟议的研究中，博士。琼斯和弗洛雷斯将有效作为多个主要研究人员进行协作。他们将与共同投资者一起与其他肝肝硬化网络（LCN）的成员开发NAFLD的精确，个性化方法预测和HCC风险分层专门针对拉丁美洲人，这是一个脆弱的人群疾病负担。在AIM 1中，博士。弗洛雷斯（Flores）和琼斯（Jones）将利用两项研究的现有数据（UCLA Atlas 社区卫生计划和美国国立卫生研究院所有研究计划）（GWAS），现象整个关联研究，并在NAFLD的人中创建多基因风险评分。我们所有人 Atlas旨在让各种参与者招募，以确保精确医学的包容性和普遍性研究。因此，拟议的研究代表了NAFLD中最大，种族最多的GWA，1999年患有NAFLD的人已经确定。我们将定义已知和新颖单曲之间的关系核苷酸多态（SNP）和NAFLD，NASH，NAFLD-CIRRHOSIS和NAFLD-HCC的风险，由种族，原产地和遗传血统。与LCN调查人员合作。弗洛雷斯和琼斯将招募拉丁裔参与者NAFLD参加一项前瞻性病例对照研究，旨在表征基因已知和新型遗传NAFLD相关的SNP与环境风险之间的环境相互作用包括艾滋病毒，糖尿病和代谢综合征在内的因素。他们将参与新的和现有的LCN队列参与者以及参与者参加了迈阿密大学（UM）现有队列的参与者洛杉矶加利福尼亚（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具有NAFLD和健康对照的新病例。我们将发展多基因风险分数结合了遗传，临床，社会文化，行为和环境特征，以预测（1）风险 NAFLD患者的肝硬化，（2）NAFLD患者的肝功能补偿，（3）HCC 有或没有肝硬化的NAFLD患者的风险。 NAFLD是美国肝硬化增长最快的原因，不成比例地影响了HCC负担最高的拉丁美洲人。通过确定最强大的风险在大型，多样化拉丁裔样本，我们可以识别那些风险最大的人并干预可修改的危险因素。