Identification of the Exposome in Fatty Liver Disease in Mexican American Families Using Genetic Correction

使用基因校正鉴定墨西哥裔美国人家庭脂肪肝中的暴露组

• 批准号: 10057266
• 负责人: John Blangero
• 金额: $ 72.86万
• 依托单位: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-27 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057266
• 关键词: 20 year old; Address; Adult; Affect; Age; Alcohol consumption; Alcoholic Fatty Liver; Behavior; Behavioral; Biological; Biological Factors; Biological Markers; Characteristics; Chemicals; Chronic; Cirrhosis; Data; Development; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Ethnic Origin; Etiology; Exhibits; Exposure to; Family; Family Study; Fatty Liver; Fatty acid glycerol esters; Fibrinogen; Fibrosis; Genetic; Genetic Variation; Genotype; Gills; Hepatitis Viruses; Heritability; High Prevalence; Hispanics; Human; Individual; Infectious Agent; Insulin Resistance; Lead; Life; Life Style; Lipids; Liver; Liver Cirrhosis; Liver Failure; Liver Fibrosis; Liver diseases; Magnetic Resonance Imaging; Measurement; Measures; Mexican Americans; Minority Groups; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Participant; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Physical activity; Plasma; Population; Predisposing Factor; Prevalence; Preventive measure; Preventive treatment; Primary carcinoma of the liver cells; Public Health; Reporting; Research Project Grants; Risk; Risk Factors; Role; Signal Transduction; Site; Socioeconomic Factors; South Texas; Spatial Distribution; Speed; Steatohepatitis; Technology; Time; Toxin; Transaminases; base; chronic liver disease; clinically relevant; cohort; design; dietary; disorder risk; epigenomics; ethnic minority population; genetic approach; genetic pedigree; genome sequencing; genome wide methylation; health disparity populations; high dimensionality; improved; lipidomics; liver imaging; liver inflammation; liver injury; mRNA sequencing; medically underserved; member; metabolomics; microbiome; non-alcoholic fatty liver disease; non-genetic; novel; novel strategies; pollutant; recruit; response; sex; transcriptome; transcriptomics; whole genome

PROJECT SUMMARY Fatty liver disease (FLD) is a major public health issue affecting millions of people worldwide. Chronic FLD is defined by excess liver fat (hepatic steatosis) and can lead to a more profound disease state of steatohepatitis (SH) that may be reflected in hepatic fibrosis (including severe cirrhosis at the extreme). SH can lead to liver failure or hepatocellular carcinoma (HCC). Multiple risk factors predispose individuals to the development of FLD including 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 both endogenous (e.g., infectious agents such as hepatitis viruses, microbiome variability) and exogenous environmental factors (e.g., exposure to pollutants/contaminants/toxins). Mexican Americans are disparately impacted by nonalcoholic FLD with some of the highest observed prevalences in the world and exhibit a prevalence of cirrhosis that is 9 times the national average. Although there is a heritable component of FLD risk, the dramatic increase FLD and HCC prevalence over the past 20 years clearly points to a major role for environmental factors since genetic variation is effectively constant on such a timescale. In this project, we will use high-dimensional omic characterization of Mexican Americans living in South Texas to assess the FLD-relevant environmentally determined exposome. We will recruit 1,000 participants from the longitudinal San Antonio Mexican American Family Study (SAMAFS) to undergo magnetic resonance imaging (MRI) to obtain measures of liver fat and liver fibrosis. Each participant has previously been completely genetically characterized by whole genome sequencing, and the WGS data will be employed to optimally identify the exposome for FLD risk in a minority population. To achieve these objectives, we will: (I) perform MRI-based measures of liver fat/fibrosis and omic characterization of 1,0000 individuals from large extended SAMAFS pedigrees, including metabolomic profiling, lipidomic profiling, epigenomic analysis, and transcriptomic sequencing; (II) detect environmental effects on FLD risk using a novel statistical genetic approach to maximize systematic environmental signals and search for environmental factors reflected in high-dimensional metabolomic/lipidomic, epigenomic, and transcriptomic biomarkers that are correlated with FLD risk; (III) characterize/classify environmental signals with regard to major environmental domains through the identification of non-random spatial distribution, or correlation with known components such as dietary behavior, socioeconomic factors, exogenous exposures, etc.; (IV) detect genotype x environment interactions using the omic data to detect genetic factors involved in the differential response of FLD risk to novel environmental factors. Overall, the ability to identify novel environmental determinants of chronic liver disease risk in an ethnic minority population provides a major opportunity to speed the development of improved targeted treatments.

项目总结 脂肪肝(FLD)是影响全球数百万人的重大公共卫生问题。慢性FLD是 由过量的肝脏脂肪(肝脏脂肪变性)定义，可导致更严重的脂肪性肝炎 (Sh)这可能反映在肝纤维化(包括严重的肝硬变)。SH可致肝 失败或肝细胞癌(HCC)。多种危险因素使个体易患FLD 包括生物因素(肥胖、胰岛素抵抗、2型糖尿病)人口统计特征(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、饮食行为和身体状况 活性)，以及内源性(例如，肝炎病毒、微生物组变异性等感染性因素)和 外源环境因素(例如，接触污染物/污染物/毒素)。墨西哥裔美国人 受到非酒精性脂肪肝的不同影响，具有世界上一些最高的观察到的发病率，并展示了 肝硬变患病率是全国平均水平的9倍。尽管FLD有一种可遗传的成分 风险，在过去20年中，FLD和肝癌患病率的急剧上升清楚地表明， 环境因素，因为遗传变异在这样的时间尺度上实际上是恒定的。 在这个项目中，我们将使用生活在南得克萨斯州的墨西哥裔美国人的高维组学特征 评估与FLD相关的环境决定的暴露。我们将从以下人员中招募1000名参与者 圣安东尼奥墨西哥裔美国人家庭纵向研究(SAMAFS)将接受磁共振成像 (MRI)以获得肝脏脂肪和肝纤维化的测量结果。每个参与者之前都完全 以全基因组测序为特征的遗传学特征，WGS数据将被用于最佳识别 少数民族人群中FLD风险的暴露。为了实现这些目标，我们将：(I)进行以核磁共振为基础的 10000名大范围扩大SAMAFS人群的肝脏脂肪/纤维化测量和组学特征 家系，包括代谢组分析、脂组分析、表观基因组分析和转录组分析 测序；(Ii)使用新的统计遗传方法检测环境对FLD风险的影响，以最大限度地 系统的环境信号和高维反映的环境因素搜索 与FLD风险相关的代谢/脂肪组、表观基因组和转录组生物标志物；(Iii) 通过以下方式对主要环境领域的环境信号进行表征/分类 识别非随机的空间分布，或与诸如饮食行为等已知成分的相关性， 社会经济因素、外源暴露等；(Iv)利用 基因组数据，以检测涉及FLD风险对新环境因素的差异反应的遗传因素。 总体而言，识别少数民族慢性肝病风险的新环境决定因素的能力 人口为加快改进靶向治疗的发展提供了一个重大机会。