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.

项目摘要 脂肪肝病（FLD）是影响全球数百万人的主要公共卫生问题。慢性FLD是 由过量的肝脏脂肪（肝脂肪变性）定义，可能导致更深刻的疾病脂肪性肝炎状态 （SH）可能反映在肝纤维化中（包括极端的肝硬化）。 SH可以导致肝脏 衰竭或肝细胞癌（HCC）。多种危险因素使个人倾向于发展FLD 包括生物学因素（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的变量（例如酒精摄入，饮食行为和身体 活性），以及内源性（例如传染剂，例如肝炎病毒，微生物组变异性）和 外源环境因素（例如，暴露于污染物/污染物/毒素）。墨西哥裔美国人是 受到世界上一些最高观察到的患病率的非酒精FLD的影响，并展示 肝硬化的患病率是全国平均水平的9倍。虽然FLD有一个可遗传的组成部分 风险，在过去20年中，FLD和HCC患病率的急剧增加显然表明 环境因素由于遗传变异在这种时间尺度上有效恒定。 在这个项目中，我们将使用居住在南德克萨斯州的墨西哥裔美国人的高维度特征 评估与FLD相关的环境确定的释放组。我们将从 纵向圣安东尼奥墨西哥裔美国家庭研究（SAMAFS）进行磁共振成像 （MRI）获得肝脏脂肪和肝纤维化的测量。每个参与者以前已经完全 通过整个基因组测序的遗传学特征，将使用WGS数据来最佳识别 少数族裔人口中FLD风险的剥离。为了实现这些目标，我们将：（i）执行基于MRI的目标 来自大型SAMAFS的1,0000个个体的肝脂肪/纤维化和OMIC表征的度量 谱系，包括代谢组分析，脂肪组分析，表观基因组分析和转录组学 测序； （ii）使用一种新型的统计遗传方法检测对FLD风险的环境影响，以最大化 系统的环境信号和搜索在高维的环境因素 与FLD风险相关的代谢组/脂肪组，表观基因组和转录组生物标志物； （iii） 通过通过该主要环境领域来表征/分类环境信号 鉴定非随机空间分布或与已知组成部分（例如饮食行为）相关， 社会经济因素，外源性暴露等； （iv）使用该基因型X X环境相互作用 OMIC数据检测FLD风险对新环境因素的差异反应涉及的遗传因素。 总体而言，识别少数民族慢性肝病风险的新型环境决定因素的能力 人口提供了一个重要的机会，可以加快改进目标治疗的发展。