Genetic Modifiers of Liver Disease Severity in Alagille Syndrome

描述（由申请人提供）： 这是一项旨在确定Alagille综合征（AGS）患者肝脏疾病严重程度的临床相关调节因子的建议。AGS是一种常染色体显性、多系统、非特异性表达的疾病，由两种Notch信号通路基因之一突变引起。在95%的患者中发现了Jagged1（JAG1）突变，而Notch2突变不到1%。AGS引起与肝脏、心脏、肾脏和血管畸形相关的显著发病率。AGS中的肝脏疾病的病理特征是肝内胆管缺乏，导致胆汁淤积，范围从非常轻微（亚临床，仅肝酶生化异常）到严重，在这种情况下，肝损伤是广泛的，需要移植。肝脏疾病导致的死亡率约为5%。高度可变的表现力与有助于表现力的修正因素的存在是一致的。我们假设肝脏疾病的严重程度有遗传修饰剂。我们提出了一个多管齐下的方法来识别这些遗传修饰剂。使用我们的AGS和JAG1突变患者的良好特征队列，我们将比较轻度肝病患者与重度肝病患者，以寻找两组之间基因组差异的证据。认识到为拟议研究获得足够把握度的重要性，我们将积极招募更多患者。我们将使用多种技术来寻找轻度肝病患者与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相关性。我们将使用随机tagSNP和特定基因组区域（候选基因）的SNP进行全基因组关联研究。我们预计，确定肝脏疾病严重程度的修正因素将具有超越Alagille综合征患者的影响，并可能指向与胆汁淤积相关的其他疾病中肝脏疾病严重程度的修正因子。

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.