Genetic Modifiers of Liver Disease Severity in Alagille Syndrome

阿拉吉尔综合征肝病严重程度的基因修饰

• 批准号: 8090799
• 负责人: Nancy Bettina Spinner
• 金额: $ 15.51万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090799
• 关键词: Affect; Alagille Syndrome; Attention; Biochemical; Candidate Disease Gene; Cardiac; Cholestasis; Clinical; Collaborations; Copy Number Polymorphism; Databases; Development; Disease; Disease Progression; Enzymes; Family; Genes; Genetic; Genomics; Hepatic; Housing; Individual; International; Intrahepatic bile duct; Italy; Laboratories; Lead; Liver; Liver diseases; Methodology; Morbidity - disease rate; Mutation; Notch Signaling Pathway; Online Mendelian Inheritance In Man; Pathway interactions; Patients; Pattern; Poland; Records; Recruitment Activity; Research Personnel; Severities; Severity of illness; Signaling Pathway Gene; Spain; Staging; Stratification; System; Techniques; Testing; Transplantation; Variant; base; clinically relevant; cohort; disease phenotype; genome wide association study; genome-wide; improved; kidney vascular structure; liver transplantation; malformation; mortality; outcome forecast

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.

项目摘要 这是一项建议，旨在识别患有肝病严重程度的临床相关修饰符 Alagille综合征（AGS）AGS是一种常染色体显性，多系统，可变的疾病。 两个Notch信号通路基因之一中的突变。在95％ Notch2的患者和突变少于1％。 AGS引起与肝脏相关的明显发病率， 心脏，肾脏和血管畸形。 AG中的肝病在病理上的特征是 肝内胆管较弱，导致胆汁淤积，范围从非常温和的范围 肝酶的生化异常至严重，在这种情况下，肝脏损害是广泛的，并且 需要移植。由于肝病而导致的死亡率约为5％。高度可变的表达性是一致的 存在导致表现力的修改因素的存在。我们假设存在遗传 肝病严重程度的修饰符。我们提出了一种多管齐下的方法来识别这些方法 遗传修饰符。使用我们良好的AGS和JAG1突变患者的同类队列，我们​​将 将轻度肝病患者与严重肝病患者进行比较，以寻找基因组的证据 两组之间的差异。认识到为拟议中获得足够权力的重要性 研究，我们将积极招募其他患者。我们将使用多种技术来寻找遗传 轻度肝病患者与严重肝病患者之间的差异。我们将测试 拷贝数变体与肝病严重程度的关联。我们将进行全基因组协会 在特定基因组区域（候选基因）中使用随机TAGSNP和SNP进行研究。我们预料到这一点 识别肝病严重程度的修饰因子将具有超出阿拉吉综合征的影响 患者，并且可能指向与胆汁淤积有关的其他疾病中肝病严重程度的修饰。