Genetic determinants of NAFLD severity and progression

NAFLD 严重程度和进展的遗传决定因素

基本信息

批准号：
8712478
负责人：
Johanna K DiStefano
金额：
$ 56.24万
依托单位：
TRANSLATIONAL GENOMICS RESEARCH INST
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-25 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712478
关键词：
Accounting Affect Bioinformatics Biological Biopsy Caucasians Caucasoid Race Characteristics Cirrhosis Clinic Clinical Data Development Diet Disease Disease Progression Enrollment Ethnic Origin Family Fatty Liver Fatty acid glycerol esters Fibrosis Gene Expression Gene Expression Profiling Genes Genetic Genetic Determinism Genetic Polymorphism Genomic DNA Genotype Goals Haplotypes Heart Hepatic Histologic Histology Individual Inflammation Insulin Resistance Knowledge Laboratories Lead Least-Squares Analysis Life Linear Models Liver Liver diseases Logistic Regressions Measurement Measures Mediating Medical center Modeling Non-Insulin-Dependent Diabetes Mellitus Nutrition management Obesity Outcome Participant Pathway Analysis Patients Phospholipase Physiology Predisposition Prevention strategy Quantitative Trait Loci RNA RNA Sequences Regression Analysis Risk Sampling Sampling Studies Severities Severity of illness Staging Steatohepatitis Techniques Testing United States Variant Weight maintenance regimen base clinical phenotype genetic association genetic variant genome-wide innovation liver biopsy liver transplantation mRNA Expression non-alcoholic fatty liver nonalcoholic steatohepatitis predictive modeling trait treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) results from excessive accumulation of fat in the liver. By itself, hepatic fat accumulation is not life-threatening, but a significant proportion of NAFLD patients progress to more severe forms of the disease characterized by inflammation, fibrosis, and cirrhosis, a condition known as nonalcoholic steatohepatitis (NASH). Although some factors, such as diet, obesity, insulin resistance, and ethnicity, have been associated with hepatic fat storage, clinical characteristics predicting NAFLD progression to more severe forms of fatty liver disease have not yet been identified. Further, little is known of the underlying physiology governing disease progression, and this gap in knowledge is a barrier to predicting which NAFLD patients will develop fibrosis and cirrhosis. The overall plan for this project, therefore, is to identify factors that predict progression of NAFLD to more severe forms of the disease. The specific goals of this study are to first evaluate the relationship between individual and composite predictors of NAFLD progression to steatohepatitis, fibrosis, and cirrhosis. Next, we will utilize a genome-wide approach to genotype 1M markers in 2075 obese individuals and assess association between these markers and NASH severity, as defined by histological grade of hepatic biopsy. All trait-associated markers and haplotypes will be validated in two independent study samples. Finally, we will perform RNA sequencing to measure hepatic gene expression and identify gene networks that are correlated with progressive NASH severity. We will also combine genotype and RNA sequencing data in an innovative approach to identify genetic variants associated with mRNA expression levels in liver samples comprising the entire spectrum of NAFLD stages. Completion of these aims will advance our understanding of NASH development and progression to more severe forms of the disease and may lead to better treatment and prevention strategies for at-risk individuals.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）是由肝脏中脂肪过度积累引起的。肝脏脂肪堆积本身并不危及生命，但很大一部分 NAFLD 患者会发展为更严重的疾病，其特征是炎症、纤维化和肝硬化，即非酒精性脂肪性肝炎 (NASH)。尽管饮食、肥胖、胰岛素抵抗和种族等一些因素与肝脏脂肪储存有关，但预测 NAFLD 进展为更严重的脂肪肝疾病的临床特征尚未确定。此外，人们对控制疾病进展的潜在生理学知之甚少，这种知识差距是预测哪些 NAFLD 患者将发展为纤维化和肝硬化的障碍。因此，该项目的总体计划是确定预测 NAFLD 进展为更严重疾病的因素。本研究的具体目标是首先评估 NAFLD 进展为脂肪性肝炎、纤维化和肝硬化的个体和复合预测因子之间的关系。接下来，我们将利用全基因组方法对 2075 名肥胖个体的 1M 标记进行基因分型，并评估这些标记与 NASH 严重程度（根据肝活检的组织学分级定义）之间的关联。所有性状相关标记和单倍型都将在两个独立的研究样本中得到验证。最后，我们将进行 RNA 测序来测量肝脏基因表达并识别与进行性 NASH 严重程度相关的基因网络。我们还将以创新方法结合基因型和 RNA 测序数据，以确定与包含 NAFLD 各个阶段的肝脏样本中 mRNA 表达水平相关的遗传变异。完成这些目标将增进我们对 NASH 发展和进展为更严重疾病形式的理解，并可能为高危个体提供更好的治疗和预防策略。