Epigenetic markers of severity in nonalcoholic fatty liver disease

项目总结/摘要 非酒精性脂肪性肝病（NAFLD）是由肝脏中脂肪的过度积累（脂肪变性）引起的。一 NAFLD患者的亚组也将发展为脂肪性肝炎、纤维化和肝硬化，这与 肝硬化的风险增加，肝脏相关的发病率和死亡率增加。的临床结局 同时发生肝细胞损伤和肝脏炎症的NAFLD患者与 对于单纯性脂肪变性的个体，迄今为止，临床特征和实验室值还没有用 用于预测NAFLD的疾病严重程度。此外，非均相的分子机制 NAFLD的结果仍然知之甚少，这限制了疾病的准确诊断和治疗。 因此，一个重要的临床挑战是区分那些NAFLD患者， 从那些不会发展临床严重形式的脂肪肝疾病。新出现的证据支持 表观遗传因素的作用，特别是DNA甲基化，在NAFLD的发展，这可能与 环境暴露与病理生理机制。该项目的总体目标是 表征DNA甲基化在NAFLD纤维化发展中的作用。具体目标是 研究首先进行DNA甲基化分析以识别差异甲基化的CpG位点 使用线性混合效应回归分析无纤维化的NAFLD和有纤维化的NAFLD之间的差异。我们将遵循 在来自同一队列的个体的独立样本中， 以及来自NASH临床研究网络（CRN）的参与者，使用与 年龄、性别和种族匹配的发现队列。然后，我们将整合来自高通量RNA的数据， 对来自发现队列的肝活检组织进行DNA甲基化结果测序，以确定 受甲基化状态的协同影响并与纤维化的存在相关。最后我们将 联合收割机已经从全基因组基因分型获得的数据和DNA甲基化分析的结果 以鉴定顺式甲基化数量性状基因座（meQTL）。DNA调控关键位点的表征 甲基化及其对基因表达的相关影响将提高我们对生物学的理解， 潜在的NAFLD相关纤维化。这些信息可能会导致识别新的目标， 治疗性干预和/或改进的方法，用于鉴定可能发展成NAFLD的NAFLD患者， 并发纤维化和/或肝硬化。鉴于NAFLD的巨大公共卫生负担， 由于肥胖症患病率的上升， 促进开发用于治疗和预防 疾病

PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) results from excessive accumulation of fat in the liver (steatosis). A subset of NAFLD patients will also develop steatohepatitis, fibrosis, and cirrhosis, which is associated with a heightened risk for liver cirrhosis and increased liver-related morbidity and mortality. Clinical outcomes for NAFLD patients with coincident hepatocyte injury and liver inflammation are substantially worse compared to individuals with simple steatosis, yet to date, clinical characteristics and laboratory values have not been useful for predicting disease severity in NAFLD. Further, the molecular mechanisms underlying the heterogeneous outcomes of NAFLD remain poorly understood, which limits accurate diagnosis and treatment of the disease. An important clinical challenge, therefore, is to distinguish those patients with NAFLD who are more likely to develop clinically severe forms of fatty liver disease from those who will not. Emerging evidence supports a role for epigenetic factors, particularly DNA methylation, in the development of NAFLD, which may link environmental exposures with pathophysiological mechanisms. The overall goal for this project is to characterize the role of DNA methylation in the development of NAFLD fibrosis. The specific aims of this study are to first perform DNA methylation profiling to identify CpG sites that are differentially methylated between NAFLD without fibrosis and NAFLD with fibrosis using linear mixed effects regression. We will follow up on the most differentially methylated CpG loci in an independent sample of individuals from the same cohort as well as participants from the NASH Clinical Research Network (CRN) using the same design as the discovery cohort matched for age, sex, and ethnicity. We will then integrate data from high throughput RNA sequencing of liver biopsies from the discovery cohort with DNA methylation results to identify genes that are coordinately affected by methylation status and associated with the presence of fibrosis. Finally, we will combine already acquired data from genome-wide genotyping and results from the DNA methylation analyses to identify cis methylation quantitative trait loci (meQTLs). Characterization of the key sites regulated by DNA methylation and the associated effects on gene expression will improve our understanding of the biology underlying NAFLD-related fibrosis. Such information may lead to the identification of novel targets for therapeutic intervention and/or improved methods for identifying NAFLD patients who will likely develop coincident fibrosis and/or cirrhosis. Given the substantial public health burden of NAFLD, which is increasing at alarming rates due to the rising prevalence of obesity, novel therapeutic targets are urgently needed to facilitate the development of improved pharmacological therapies for the treatment and prevention of the disease.