Mechanisms of Advanced NAFLD Disparities in Hispanics: A Multi-level Analysis

西班牙裔晚期 NAFLD 差异的机制：多层次分析

• 批准号: 10530687
• 负责人: VERONICA WENDY SETIAWAN
• 金额: $ 61.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530687
• 关键词: Affect; Automobile Driving; Bioinformatics; Biological; Cells; Cholesterol; Cirrhosis; Clinical; Clinical Data; Complex; County; Data; Development; Diagnostic; Dietary Factors; Disease; Disease Progression; Disparity; Enrollment; Environment; Environmental Risk Factor; Ethnic Origin; Ethnic Population; Etiology; Evaluation; Fibrosis; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Goals; Hepatic; Heterogeneity; High Prevalence; Hispanic; Hispanic Populations; Hospitals; Immigrant; Immune; Immune Targeting; Immune response; Immunologic Factors; Incidence; Inflammation; Intake; Life Style; Lipids; Liver; Liver Fibrosis; Los Angeles; Metabolic; Methods; Mitochondria; Modernization; Morbidity - disease rate; Natural History; Neighborhoods; Not Hispanic or Latino; Nuclear; Pathology; Patients; Performance; Peripheral; Phenotype; Plasma Proteins; Population; Population Heterogeneity; Prevalence; Primary carcinoma of the liver cells; Questionnaires; RNA; Race; Recording of previous events; Research; Risk Factors; Severities; Severity of illness; Societies; Specimen; Subgroup; Tissue-Specific Gene Expression; Ultrasonography; chronic liver disease; contextual factors; dietary; disease disparity; disorder risk; ethnic disparity; ethnic diversity; gene discovery; genetic variant; health disparity; high risk; high risk population; improved; innovation; insight; lifestyle factors; liver inflammation; liver transplantation; migration; mortality; multidisciplinary; multilevel analysis; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; outcome prediction; polygenic risk score; prospective; protein biomarkers; protein expression; racial population; recruit; response; single-cell RNA sequencing; social; social factors; social influence; sociodemographic factors; therapeutic target; trait; transcriptomic profiling; transcriptomics

PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH) is a major cause of chronic liver disease that may progress to cirrhosis and hepatocellular carcinoma (HCC). Considering the prevalence, particularly among Hispanics, understanding the etiology and mechanisms of this disease by race/ethnicity is imperative. We have established a multidisciplinary team to comprehensively characterize the dynamic interplay of multiple factors (genetics, lifestyle, environmental and immune factors) in NAFLD/NASH and the underlying mechanisms driving incidence, severity and progression that result in health disparities in Hispanics. We will identify factors associated with NAFLD development and progression in Hispanics and non- Hispanic whites (NHW) in Los Angeles County (LAC). The large immigrant populations in LAC offer unique perspectives and opportunities to examine health disparities in Hispanics. We will enroll 2,000 patients (1,000 Hispanics and 1,000 NHW) with FibroScan-confirmed advanced (>F2) and mild (≤F1) hepatic fibrosis and 1,000 matched controls without ultrasonographic evidence of NAFLD recruited from the LAC and USC Keck Hospitals. We will collect biological specimens, clinical and detailed questionnaire data for sociodemographic and risk factors and use geospatial approaches to ascertain social and neighborhood-related factors. Case groups will be followed prospectively for disease progression. Our specific aims are 1) to determine the contribution of lifestyle, clinical, social/environmental factors and genetics (nuclear and mitochondrial) to ethnic disparities in NAFLD risk, disease severity (advanced/mild fibrosis) in Hispanics and NHW; 2) to examine how differential gene expression revealed by scRNA-transcriptomic profiling of circulating innate immune cells in NAFLD varies according to polygenic risk scores and dietary factors; utilize bioinformatics approach to identify plasma proteins with diagnostic and predictive accuracy for NAFLD severity and progression; 3) to identify high-risk groups for NAFLD risk and progression by integrating genetics, lifestyle, clinical, social and contextual factors in Hispanics and NHW using an innovative latent variable analysis. Our study will culminate in novel, comprehensive, and innovative characterization of multi-level factors associated with phenotypic spectrum of NAFLD and disease progression and contribute significantly to the understanding of the etiology and mechanisms that influence disparities in NAFLD in high-risk Hispanic population.

项目概要/摘要 非酒精性脂肪性肝病 (NAFLD) 导致非酒精性脂肪性肝炎 (NASH) 的主要原因 可能发展为肝硬化和肝细胞癌 (HCC) 的慢性肝病。考虑到 患病率，特别是在西班牙裔中，了解这种疾病的病因和机制 种族/民族是必要的。我们建立了一个多学科团队来全面表征 NAFLD/NASH 中多种因素（遗传、生活方式、环境和免疫因素）的动态相互作用 以及导致发病率、严重程度和进展的潜在机制，从而导致健康差异 西班牙裔。我们将确定与西班牙裔和非非酒精性脂肪肝 (NAFLD) 发生和进展相关的因素。 洛杉矶县 (LAC) 的西班牙裔白人 (NHW)。拉丁美洲和加勒比地区大量的移民人口提供了独特的优势 检查西班牙裔健康差异的观点和机会。我们将招募 2,000 名患者（1,000 西班牙裔和 1,000 名 NHW）患有 FibroScan 证实的晚期（>F2）和轻度（≤F1）肝纤维化和 1,000 从 LAC 和 USC Keck 医院招募没有 NAFLD 超声证据的对照对照。 我们将收集生物样本、临床和详细的社会人口统计学和风险问卷数据 因素并使用地理空间方法来确定社会和邻里相关因素。案例小组将 前瞻性地跟踪疾病进展。我们的具体目标是 1) 确定贡献 生活方式、临床、社会/环境因素和遗传学（核和线粒体）对种族差异的影响 西班牙裔和 NHW 中的 NAFLD 风险、疾病严重程度（晚期/轻度纤维化）； 2）检查如何区分 NAFLD 循环先天免疫细胞的 scRNA 转录组分析揭示的基因表达存在差异 根据多基因风险评分和饮食因素；利用生物信息学方法鉴定血浆蛋白 对 NAFLD 严重程度和进展具有诊断和预测准确性； 3）识别高危人群 通过整合西班牙裔的遗传、生活方式、临床、社会和背景因素来了解 NAFLD 风险和进展 NHW 使用创新的潜变量分析。我们的研究将以新颖、全面和 与 NAFLD 和疾病表型谱相关的多层次因素的创新表征 进展并极大地有助于理解影响的病因和机制 高危西班牙裔人群中 NAFLD 的差异。