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: 7883529
• 负责人: Nancy Bettina Spinner
• 金额: $ 69.01万
• 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/7883529
• 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

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.

描述（由申请人提供）： 这是一项旨在确定 Alagille 综合征 (AGS) 患者肝病严重程度的临床相关修饰因子的提案。AGS 是一种常染色体显性、多系统、表达可变的疾病，由两个 Notch 信号通路基因之一的突变引起。 95% 的患者存在 Jagged1 (JAG1) 突变，不到 1% 的患者存在 Notch2 突变。 AGS 导致与肝脏、心脏、肾脏和血管畸形相关的显着发病率。 AGS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广泛，需要移植。肝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饰因素的存在是一致的。我们假设肝脏疾病的严重程度存在遗传修饰因素。我们提出了一种多管齐下的方法来鉴定这些遗传修饰剂。利用我们充分表征的 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，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功效的重要性，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关联。我们将使用随机标签SNP和特定基因组区域（候选基因）中的SNP进行全基因组关联研究。我们预计，确定肝病严重程度的改变因素将不仅仅对 Alagille 综合征患者产生影响，并且可能指出其他与胆汁淤积相关疾病的肝病严重程度的改变因素。