Epigenetic markers of severity in nonalcoholic fatty liver disease

非酒精性脂肪肝疾病严重程度的表观遗传标记

• 批准号: 9165134
• 负责人: Johanna K DiStefano
• 金额: $ 57.28万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9165134
• 关键词: Address; Affect; Age; Alcohols; Alleles; Biology; Characteristics; Cicatrix; Cirrhosis; Clinical; Clinical Research; DNA Methylation; Data; Dependence; Development; Disease; Environmental Exposure; Epigenetic Process; Ethnic Origin; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Gene Expression; Genes; Genetic; Genotype; Glycosylated hemoglobin A; Goals; Hepatic; Hepatocyte; High-Throughput RNA Sequencing; Immune; Individual; Inflammation; Injury; Insulin Resistance; Laboratories; Lead; Least-Squares Analysis; Linear Regressions; Link; Liver; Liver Cirrhosis; Liver diseases; Measurement; Mediating; Methods; Methylation; Minor; Modeling; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Participant; Pathogenesis; Pathway Analysis; Patients; Prevalence; Public Health; Quantitative Trait Loci; Refit; Regression Analysis; Risk; Role; Sampling; Severities; Severity of illness; Site; Staging; Steatohepatitis; Testing; Therapeutic Intervention; Variant; accurate diagnosis; base; bead chip; biobank; cohort; design; disorder prevention; drug development; epigenetic marker; follow-up; genetic variant; genome wide methylation; genome-wide; improved; liver biopsy; liver inflammation; mortality; new therapeutic target; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; patient subsets; prevent; sex; transcriptome sequencing

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.

项目摘要/摘要 非酒精性脂肪肝病（NAFLD）是由于肝脏中脂肪过量积累（脂肪变性）引起的。一个 NAFLD患者的子群还将发展出脂肪性肝炎，纤维化和肝硬化，这与A 肝肝硬化的风险增加，并增加了与肝有关的发病率和死亡率。临床结果 与肝细胞损伤和肝炎的NAFLD患者相比 具有简单脂肪变性的个体，但迄今为止，临床特征和实验室值尚未有用 用于预测NAFLD的疾病严重程度。此外，异质性的分子机制 NAFLD的结果仍然很少了解，这限制了对疾病的准确诊断和治疗。 因此，一个重要的临床挑战是​​区分那些更有可能的NAFLD患者 从那些不会的患者中发展出临床上严重的脂肪肝病。新兴证据支持 表观遗传因素，尤其是DNA甲基化的作用，在NAFLD的发展中，这可能会联系起来 具有病理生理机制的环境暴露。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。这个特定的目的 研究首先进行DNA甲基化分析，以鉴定差异甲基化的CpG位点 在没有纤维化的NAFLD和使用线性混合效应回归的NAFLD之间。我们将跟随 从同一队列的独立样本中的最差异甲基化的CpG基因座上 以及NASH临床研究网络（CRN）的参与者，都使用与 发现队列与年龄，性别和种族相匹配。然后，我们将整合来自高吞吐量RNA的数据 从发现队列中与DNA甲基化结果对肝活检的测序，以鉴定基因 受甲基化状态的协调影响，与纤维化的存在有关。最后，我们会的 将已经从全基因组基因分型和DNA甲基化分析结果的已获得的数据结合在一起 识别顺式甲基化定量性状基因座（MEQTL）。由DNA调节的关键位点的表征 甲基化和对基因表达的相关影响将改善我们对生物学的理解 基础与NAFLD相关的纤维化。这样的信息可能会导致确定新的目标 治疗干预和/或改进的方法来识别可能发展的NAFLD患者 一致的纤维化和/或肝硬化。鉴于NAFLD的实质性公共卫生负担正在增加 由于肥胖的患病率上升而引起的令人震惊的率，迫切需要新的治疗靶标 促进改进的药理疗法以治疗和预防 疾病。