Genetic Modifiers of Liver Disease Severity in Alagille Syndrome

项目总结 这是一个建议，以确定临床上相关的修饰物的严重程度的肝病患者 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信号通路基因中的一个发生突变。Jagged1(JAG1)基因突变在95%的 患者和Notch2基因突变不到1%。AGS会导致与肝脏相关的显著发病率， 心脏、肾脏和血管畸形。AGS中的肝病的病理特征是 肝内胆管稀少，导致胆汁淤积，范围从非常轻微(亚临床仅 肝酶生化异常)到严重，在这种情况下，肝脏损害是广泛的， 移植是必需的。因肝病导致的死亡率约为5%。高度可变的表现力是一致的 以及有助于表现力的修饰因素的存在。我们假设有一种基因 肝脏疾病严重程度的修饰物。我们提出了一种多管齐下的方法来识别这些 遗传修饰物。利用我们特征良好的AGS和JAG1突变患者队列，我们将 比较轻度肝病患者和重度肝病患者，寻找基因组证据 两组间的差异。认识到为拟议的 研究后，我们将积极招募更多的患者。我们将使用多种技术来寻找基因 轻度肝病患者与重度肝病患者的差异。我们将测试 拷贝数变异与肝病严重程度的关系。我们将开展全基因组联合 利用随机标签SNPs和特定基因组区域(候选基因)中的SNPs进行研究。我们预料到 确定肝病严重程度的修正因素将具有超越Alagille综合征的意义 患者，并可能指出与胆汁淤积相关的其他疾病的肝病严重程度的修饰物。

PROJECT SUMMARY 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.