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

项目摘要 脂肪肝（FLD）是影响全球数百万人的主要公共卫生问题。慢性FLD是 定义为肝脏脂肪过多（肝脂肪变性），并可导致更严重的脂肪性肝炎疾病状态 (SH)这可能反映在肝纤维化（包括极端的严重肝硬化）。SH可导致肝脏 失败或肝细胞癌（HCC）。多种危险因素使个体易患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、饮食行为和身体状况 活性），和内源性（例如，感染因子，如肝炎病毒、微生物组变异性）， 外部环境因素（例如，接触污染物/污染物/毒素）。墨西哥裔美国人 受非酒精性FLD的严重影响，在世界上观察到的患病率最高， 肝硬化患病率是全国平均水平的9倍尽管FLD有遗传因素 在过去的20年里，FLD和HCC患病率的急剧增加清楚地表明， 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，我们将使用高维度的组学表征墨西哥裔美国人生活在南德克萨斯州 评估FLD相关的环境决定性问题。我们将从 纵向圣安东尼奥墨西哥裔美国人家庭研究（SAMAFS）进行磁共振成像 (MRI)以获得肝脂肪和肝纤维化的测量值。每个参与者之前都已经完全 通过全基因组测序进行遗传特征分析，WGS数据将用于最佳识别 在少数人群中存在FLD风险的麻烦。为了实现这些目标，我们将：（一）进行基于MRI的 来自大型扩展SAMAFS的1，0000名个体的肝脏脂肪/纤维化和组学特征的测量 谱系，包括代谢组学分析、脂质组学分析、表观基因组学分析和转录组学分析。 测序;（II）使用新的统计遗传方法检测环境对FLD风险的影响，以最大化 系统的环境信号和搜索环境因素反映在高维 与FLD风险相关的代谢组学/脂质组学、表观基因组学和转录组学生物标志物;（III） 对环境信号进行表征/分类， 非随机空间分布的识别，或与已知成分如饮食行为的相关性， 社会经济因素、外源性暴露等; (IV)检测基因型x环境的相互作用，使用 组学数据，以检测参与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 人口普查为加速改进靶向治疗的发展提供了一个重要机会。

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.