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）是由肝脏中脂肪过度积累引起的。肝脏脂肪积聚本身并不危及生命，但相当一部分NAFLD患者进展为更严重的疾病形式，其特征在于炎症、纤维化和肝硬化，这是一种称为非酒精性脂肪性肝炎（NASH）的疾病。虽然一些因素，如饮食，肥胖，胰岛素抵抗和种族，已与肝脏脂肪储存，临床特征预测NAFLD进展到更严重的形式的脂肪肝疾病尚未确定。此外，对控制疾病进展的潜在生理学知之甚少，这种知识上的差距是预测哪些NAFLD患者将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进展为更严重疾病形式的因素。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，我们将在2075名肥胖个体中利用全基因组方法检测基因型1 M标志物，并评估这些标志物与NASH严重程度之间的相关性，如肝活检组织学分级所定义。将在两个独立的研究样本中验证所有性状相关标记和单倍型。最后，我们将进行RNA测序来测量肝脏基因表达，并鉴定与进行性NASH严重程度相关的基因网络。我们还将以创新的方法将联合收割机基因型和RNA测序数据相结合，以鉴定与肝脏样本中mRNA表达水平相关的遗传变异，包括NAFLD阶段的整个谱。这些目标的实现将促进我们对NASH发展和进展到更严重疾病形式的理解，并可能为高危人群提供更好的治疗和预防策略。 公共卫生相关性：患有肥胖、胰岛素抵抗和/或2型糖尿病的个体通常在肝脏中储存过量的脂肪。肝脏脂肪堆积本身并不危及生命，但一些受影响的患者会发展成更严重的脂肪肝，包括脂肪性肝炎、纤维化和肝硬化;然而，目前还没有临床措施来确定哪些人最有可能进展。这项研究将确定调节非酒精性脂肪肝疾病严重程度和进展的遗传变异，这将导致高危人群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.