Genetic determinants of NAFLD severity and progression

NAFLD 严重程度和进展的遗传决定因素

• 批准号: 8087303
• 负责人: Johanna K DiStefano
• 金额: $ 73.96万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 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/8087303
• 关键词: Accounting; Affect; Bioinformatics; Biological; Biopsy; Caucasians; Caucasoid Race; Characteristics; Cirrhosis; Clinic; Clinical; DNA; 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; Genomics; 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; 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; base; clinical phenotype; genetic association; genetic variant; genome-wide; innovation; liver biopsy; liver transplantation; mRNA Expression; non-alcoholic fatty liver; nonalcoholic steatohepatitis; nutrition; predictive modeling; trait; treatment strategy

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. PUBLIC HEALTH RELEVANCE: Individuals suffering from obesity, insulin resistance and/or type 2 diabetes often store excessive fat in the liver. By itself, hepatic fat accumulation is not life-threatening, but some affected patients will develop more severe forms of fatty liver disease including steatohepatitis, fibrosis, and cirrhosis; however, no clinical measures are yet available to identify which individuals are most likely to progress. This study will identify genetic variants that modulate severity and progression of nonalcoholic fatty liver disease, which will lead to better treatment and prevention strategies in at-risk individuals.

描述（由申请人提供）：非酒精性脂肪肝疾病（NAFLD）是由于肝脏中脂肪过量积累而导致的。就其本身而言，肝脂肪的积累并不是威胁生命的，但是很大一部分NAFLD患者会发展为以炎症，纤维化和肝硬化为特征的更严重的疾病形式，这种疾病被称为非酒精性脂肪性肝炎（NASH）。尽管某些因素，例如饮食，肥胖，胰岛素抵抗和种族，与肝脂肪储存有关，但尚未鉴定出NAFLD进展为更严重的脂肪肝病形式的临床特征。此外，关于疾病进展的潜在生理学知之甚少，知识的差距是预测哪些NAFLD患者会发展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进展到更严重疾病形式的因素。这项研究的具体目标是首先评估NAFLD进展到脂肪性肝炎，纤维化和肝硬化的个人和复合预测因子之间的关系。接下来，我们将在2075年的肥胖个体中利用全基因组的1M标记方法，并评估这些标记与NASH严重程度之间的关联，如肝活检的组织学等级所定义。所有与性状相关的标记和单倍型将在两个独立研究样本中进行验证。最后，我们将执行RNA测序以测量肝基因表达并识别与进行性NASH严重程度相关的基因网络。我们还将将基因型和RNA测序数据结合在创新的方法中，以鉴定肝样品中与MRNA表达水平相关的遗传变异，包括整个NAFLD阶段。这些目标的完成将提高我们对纳什发育和发展为更严重疾病形式的理解，并可能导致对高危个人的更好的治疗和预防策略。 公共卫生相关性：患有肥胖，胰岛素抵抗和/或2型糖尿病的人通常在肝脏中储存过多的脂肪。就其本身而言，肝脂肪的积累并不是威胁生命的，但是一些受影响的患者会发展出更严重的脂肪肝病，包括脂肪性肝炎，纤维化和肝硬化。但是，尚无临床措施来确定哪些人最有可能进步。这项研究将确定调节非酒精性脂肪肝病的严重程度和进展的遗传变异，这将导致高危个体的更好的治疗和预防策略。