Research Project 1 - Hepatocellular Genetic Epidemiology of Fatty Liver Disease in Hispanics

研究项目 1 - 西班牙裔脂肪肝病的肝细胞遗传流行病学

• 批准号: 10749787
• 负责人: JOANNE E. CURRAN
• 金额: $ 73.92万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749787
• 关键词: 20 year old; Adult; Affect; Age; Alcohol consumption; Alcoholic Fatty Liver; Apoptotic; Behavior; Behavioral; Biological Factors; Biological Markers; Cell Death; Cell Line; Cells; Cellular Stress; Characteristics; Cirrhosis; Complex Mixtures; Data; Development; Dietary Fats; Disease; Early Diagnosis; Environment; Environmental Risk Factor; Ethnic Origin; Etiology; Evaluation; Exhibits; Exposure to; Family; Family Study; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Gene Expression Profiling; Genes; Genetic; Genetic Risk; Genetic Transcription; Genome; Genotype; Gills; Goals; Hepatitis Viruses; Hepatocyte; Hispanic Populations; Image; In Vitro; Individual; Infectious Agent; Insulin Resistance; Knowledge; Life Style; Lipids; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Magnetic Resonance Imaging; Measures; Mexican Americans; Minority Groups; Modeling; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Participant; Pathway interactions; Persons; Phenotype; Physical activity; Population; Populations at Risk; Predisposing Factor; Prevalence; Primary carcinoma of the liver cells; Procedures; Property; Public Health; Reporting; Research; Research Project Grants; Risk; Risk Estimate; Risk Factors; South Texas; Speed; Steatohepatitis; Study Subject; Testing; Toxin; causal variant; chronic liver disease; cohort; dietary; disorder risk; early detection biomarkers; endophenotype; epidemiology study; fatty liver disease; feeding; genetic epidemiology; genome-wide; health disparity populations; indexing; individual variation; induced pluripotent stem cell; liver inflammation; microbiome; molecular phenotype; multiple omics; non-alcoholic fatty liver disease; novel; novel strategies; outcome disparities; pollutant; response; sex; single cell sequencing; social determinants; transcriptome sequencing

PROJECT SUMMARY Fatty liver disease (FLD) is a major public health issue that affects millions of people worldwide. The two major subtypes of FLD include alcoholic FLD (AFLD) and nonalcoholic FLD (NAFLD) although the threshold of alcohol intake for subdivision is controversial. FLD is defined by excess fat in the liver and can lead to a more profound disease state of steatohepatitis (SH) in which there is liver inflammation/damage that may be reflected in hepatic fibrosis. SH can lead to liver failure or hepatocellular carcinoma. Major risk factors predisposing individuals to the development of FLD include biological factors (obesity, insulin resistance, type 2 diabetes) demographic characteristics (e.g., sex, age and ethnicity), behavioral and lifestyle-related variables (e.g., alcohol intake, dietary behavior and physical activity), and other environmental factors (e.g., infectious agents such as hepatitis viruses, microbiome variability, exposure to pollutants/contaminants/toxins). Hispanics are disparately impacted by NAFLD with the highest observed prevalence of NAFLD in the world. Risk for NAFLD is due to a complex mixture of genetic and environmental factors and their interactions that are still largely unidentified. Quantitative endophenotypes (i.e., biomarkers that are genetically correlated with disease risk) have important properties that can speed the discovery of disease-related genetic causal factors and aid in individual-level risk estimation. Here we propose a novel deep cellular phenotyping assessment of induced pluripotent stem cell (iPSC)-derived hepatocyte response to experimental lipid overload challenge, which mimics dietary lipid overfeeding. This experimental epidemiological study will allow us to rigorously test for genotype-by-environment interactions (GEI) to better understand the etiology/mechanisms of NAFLD risk and to enhance early detection and halt progression. Specifically, we will identify novel iPSC-derived hepatocellular endophenotypes involved in NAFLD risk in Mexican Americans, a health disparity population, using a high-throughput multiomic approach. The study will use existing data and cellular biosamples from 900 participants in our longitudinal Mexican American Family Study (MAFS), who have been extensively phenotyped (including liver MRI) and genetically characterized. Our specific aims include: 1) discovery of novel hepatocellular cellular endophenotypes for NAFLD risk by quantitative genome-wide RNA sequencing and functional evaluation of hepatocytes derived from existing iPSCs in 400 subjects; (2) discovery of multivariate hepatocellular transcriptional coherence endophenotypes using single-cell sequencing; and (3) confirmation of the highest ranking NAFLD endophenotypes using MRI-derived liver fat measures from an additional 500 MAFS subjects from the same families. Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease and it disparately affects minority populations, with Hispanics being one of the highest at-risk populations. By identifying genetically determined cellular endophenotypes, we hope to speed the identification of potential causal genes in NAFLD risk and for identifying non-invasive early biomarkers of genetic risk for NAFLD.

项目概要 脂肪肝病（FLD）是影响全球数百万人的主要公共卫生问题。两大主要 FLD 的亚型包括酒精性 FLD (AFLD) 和非酒精性 FLD (NAFLD)，尽管酒精阈值 细分的摄入量存在争议。 FLD 是指肝脏中过多的脂肪，可能会导致更严重的后果。 脂肪性肝炎 (SH) 的疾病状态，其中肝脏炎症/损伤可能反映在肝脏中 纤维化。 SH 可导致肝衰竭或肝细胞癌。使个人容易出现以下情况的主要风险因素 FLD 的发展包括生物因素（肥胖、胰岛素抵抗、2 型糖尿病）、人口统计学 特征（例如性别、年龄和种族）、行为和生活方式相关变量（例如酒精摄入量、 饮食行为和体力活动）以及其他环境因素（例如肝炎等传染源） 病毒、微生物组变异、接触污染物/污染物/毒素）。西班牙裔受到不同程度的影响 NAFLD 是世界上观察到的 NAFLD 患病率最高的疾病。 NAFLD 的风险是由遗传和环境因素及其相互作用造成的。 仍然很大程度上未被识别。定量内表型（即与基因相关的生物标志物） 疾病风险）具有重要的特性，可以加速发现与疾病相关的遗传因素 并帮助进行个人层面的风险评估。在这里，我们提出了一种新颖的深度细胞表型评估 诱导多能干细胞（iPSC）衍生的肝细胞对实验性脂质超载挑战的反应， 它模仿饮食中的脂质过量喂养。这项实验性流行病学研究将使我们能够严格测试 基因型与环境的相互作用 (GEI)，以更好地了解 NAFLD 风险的病因/机制 并加强早期发现并阻止进展。具体来说，我们将鉴定新型 iPSC 衍生的 肝细胞内表型与健康差异人群墨西哥裔美国人 NAFLD 风险相关， 使用高通量多组学方法。该研究将使用来自 900 个组织的现有数据和细胞生物样本 我们纵向墨西哥裔美国人家庭研究 (MAFS) 的参与者，他们已被广泛表型分析 （包括肝脏 MRI）和遗传特征。我们的具体目标包括：1）发现新型肝细胞 通过定量全基因组 RNA 测序和功能评估确定 NAFLD 风险的细胞内表型 400 名受试者中现有 iPSC 衍生的肝细胞； (2)多元肝细胞的发现 使用单细胞测序的转录一致性内表型； (3) 最高确认 使用来自另外 500 名 MAFS 受试者的 MRI 衍生肝脏脂肪测量值对 NAFLD 内表型进行排名 来自同一个家庭。 非酒精性脂肪性肝病（NAFLD）是慢性肝病的最常见原因之一， 对少数族裔的影响不同，西班牙裔是高危人群之一。通过识别 遗传决定的细胞内表型，我们希望加快潜在因果基因的识别 NAFLD 风险和识别 NAFLD 遗传风险的非侵入性早期生物标志物。