Genetic Modifiers of Liver Disease Severity in Alagille Syndrome

项目摘要 这是一个建议，以确定临床相关的修饰符的严重程度，肝病患者 Alagille综合征（AGS）是一种常染色体显性遗传的多系统表达的疾病， Notch Signaling Pathway基因突变Jagged1（JAG1）突变存在于95%的 Notch2突变的患者不到1%。AGS引起与肝脏相关的显著发病率， 心脏、肾脏和血管畸形。AGS中的肝脏疾病的病理特征为： 肝内胆管缺乏，导致胆汁淤积，范围从非常轻度（亚临床，仅 肝酶生化异常）至重度，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%。高度可变的表现力是一致的 与有助于表现力的修正因素的存在。我们假设有遗传的 肝脏疾病严重程度的调节剂。我们提出了一个多管齐下的方法来识别这些 基因修饰剂使用我们特征明确的AGS和JAG1突变患者队列，我们将 将轻度肝病患者与重度肝病患者进行比较，以寻找基因组证据。 两组之间的差异。认识到为拟议的联合国系统获得足够的权力的重要性， 研究，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之间的差异。我们将测试 拷贝数变异与肝病严重程度的相关性。我们将进行全基因组关联 使用随机tagSNPs和特定基因组区域（候选基因）中的SNPs进行研究。我们预计 确定肝病严重程度的修饰因子将具有Alagille综合征以外的意义 患者，并可能指向其他与胆汁淤积相关的疾病中肝病严重程度的修饰符。

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.