Genetic determinants of NAFLD severity and progression

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）是由肝脏脂肪过度积累引起的。就其本身而言，肝脏脂肪积累不会危及生命，但相当比例的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，即非酒精性脂肪性肝炎（NASH）。虽然一些因素，如饮食、肥胖、胰岛素抵抗和种族，与肝脏脂肪储存有关，但预测NAFLD进展为更严重形式的脂肪性肝病的临床特征尚未确定。此外，对控制疾病进展的潜在生理学知之甚少，这方面的知识差距是预测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进展为更严重形式的疾病的因素。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综合预测因素之间的关系。接下来，我们将利用全基因组方法对2075名肥胖个体进行1M基因型标记，并评估这些标记与NASH严重程度之间的关系，根据肝活检的组织学分级来定义。所有性状相关标记和单倍型将在两个独立的研究样本中进行验证。最后，我们将进行RNA测序来测量肝脏基因表达，并确定与进行性NASH严重程度相关的基因网络。我们还将结合基因型和RNA测序数据，以一种创新的方法来识别与NAFLD整个阶段肝脏样本中mRNA表达水平相关的遗传变异。这些目标的完成将促进我们对NASH发展和发展为更严重的疾病形式的理解，并可能为高危人群提供更好的治疗和预防策略。

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.