Genetic determinants of NAFLD severity and progression

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是由肝脏脂肪过度堆积引起的。肝脏脂肪堆积本身不会危及生命，但相当大比例的NAFLD患者会进展为更严重的疾病，其特征是炎症、纤维化和硬化，这种情况被称为非酒精性脂肪性肝炎(NASH)。尽管一些因素，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肝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，这种认识上的差距是预测哪些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发展为更严重形式的疾病的因素。这项研究的具体目标是首先评估NAFLD进展为脂肪性肝炎、纤维化和肝硬变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名肥胖者的1M标记进行基因分型，并评估这些标记与肝脏活检组织学分级所定义的NASH严重程度之间的相关性。所有与性状相关的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的表达，并确定与进展性NASH严重程度相关的基因网络。我们还将以一种创新的方法将基因型和RNA测序数据结合起来，以确定与肝脏样本中mRNA表达水平相关的遗传变异，包括NAFLD分期的整个光谱。完成这些目标将促进我们对NASH发展和进展为更严重形式的疾病的了解，并可能导致对高危个人更好的治疗和预防策略。 公共卫生相关性：患有肥胖症、胰岛素抵抗和/或2型糖尿病的人通常会在肝脏中储存过多的脂肪。肝脏脂肪堆积本身不会危及生命，但一些受影响的患者会发展成更严重的脂肪性肝病，包括脂肪性肝炎、纤维化和肝硬变；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性肝病严重程度和进展的基因变异，这将导致高危个体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.