Genetic Modifiers of Liver Disease Severity in Alagille Syndrome

描述(由申请人提供)： Alagille综合征(AGS)是一种常染色体显性、多系统、可变表达的疾病，由两个Notch信号通路基因突变引起。在95%的患者中发现了Jagged1(JAG1)的突变，而Notch2的突变不到1%。AGS导致与肝脏、心脏、肾脏和血管畸形相关的显著发病率。AGS的肝脏疾病的病理特征是肝内胆管稀少，导致胆汁淤积，范围从非常轻微(亚临床仅有肝酶生化异常)到严重，在这种情况下，肝脏损伤广泛，需要进行移植。因肝病导致的死亡率约为5%。高度可变的表现力与影响表现力的修饰因子的存在是一致的。我们假设存在影响肝脏疾病严重程度的基因修饰因素。我们提出了一种多管齐下的方法来识别这些遗传修饰因子。使用我们特征良好的AGS和JAG1突变患者队列，我们将比较轻度肝病患者和严重肝病患者，以寻找两组之间基因组差异的证据。认识到获得足够的权力进行拟议研究的重要性，我们将积极招募更多的患者。我们将使用多种技术来寻找轻度肝病患者和重度肝病患者之间的遗传差异。我们将测试 拷贝数变异与肝病严重程度的关系。我们将利用随机标签SNPs和特定基因组区域(候选基因)中的SNPs进行全基因组关联研究。我们预计，确定肝病严重程度的修正因子将具有超越Alagille综合征患者的意义，并可能指出与胆汁淤积相关的其他疾病的肝病严重程度修正因子。

DESCRIPTION (provided by applicant): This is a proposal to identify clinically relevant modifiers of the severity of hepatic disease in patients with Alagille Syndrome (AGS) AGS is an autosomal dominant, multi-system, variably expressed disorder caused by mutations in one of two Notch Signaling Pathway genes. Mutations in Jagged1 (JAG1) are found in 95% of patients and mutations in Notch2 in less than 1%. AGS causes significant morbidity associated with liver, cardiac, renal and vascular malformations. The liver disease in AGS is characterized pathologically by intrahepatic bile duct paucity, with resulting cholestasis, and ranges from very mild (sub-clinical with only biochemical abnormalities of liver enzymes) to severe, in which case liver damage is extensive and a transplant is required. Mortality due to liver disease is about 5%. The highly variable expressivity is consistent with the presence of modifying factors that contribute to expressivity. We hypothesize that there are genetic modifiers of the severity of liver disease. We propose a multi-pronged approach to the identification of these genetic modifiers. Using our well-characterized cohort of patients with AGS and JAG1 mutations, we will compare patients with mild liver disease to patients with severe liver disease to look for evidence of genomic differences between the two groups. Recognizing the importance of attaining adequate power for the proposed studies, we will aggressively recruit additional patients. We will use multiple techniques to look for genetic differences between the patients with mild liver disease versus those with severe liver disease. We will test for association of copy number variants with liver disease severity. We will carry out a genome-wide association study using random tagSNPs and SNPs in specific genomic regions (candidate genes). We anticipate that identification of modifying factors for liver disease severity will have implications beyond Alagille syndrome patients, and may point to modifiers of liver disease severity in other disorders associated with cholestasis.