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

项目摘要/摘要 非酒精性脂肪性肝病(NAFLD)导致非酒精性脂肪性肝炎(NASH)是 可能进展为肝硬变和肝细胞癌的慢性肝病。考虑到 患病率，特别是在拉美裔美国人中，了解这种疾病的病因和机制 种族/民族是势在必行的。我们已经建立了一个多学科团队来全面描述 多种因素(遗传、生活方式、环境和免疫因素)在NAFLD/NASH中的动态相互作用 以及导致健康差距的发病率、严重性和进展的潜在机制 西班牙裔。我们将确定与西班牙裔和非拉美裔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庞大的移民人口提供了独特的 研究拉美裔美国人健康差异的视角和机会。我们将招募2,000名患者(1,000 西班牙人和1,000人)，纤维扫描证实的晚期(F2)和轻度(≤F1)肝纤维化和1,000人 从LAC和南加州大学凯克医院招募的没有NAFLD超声证据的匹配对照组。 我们将收集生物标本、临床和详细的社会人口学和风险问卷数据。 并使用地理空间方法来确定与社会和邻里有关的因素。案例组将 前瞻性地跟踪观察疾病进展情况。我们的具体目标是1)确定 生活方式、临床、社会/环境因素和遗传学(核和线粒体)与种族差异 拉美裔和NHW人群的NAFLD风险、疾病严重程度(晚期/轻度纤维化)；2)检查差异有多大 单链RNA转录图谱显示NAFLD患者循环天然免疫细胞的基因表达不同 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的严重程度和进展具有诊断和预测的准确性；3)识别 整合西班牙裔美国人的遗传、生活方式、临床、社会和背景因素的NAFLD风险和进展 和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水平因子的创新表征 进展，并对理解影响的病因和机制做出了重大贡献 西班牙裔高危人群中非酒精性脂肪肝的差异。

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.