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

基本信息

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
项目类别：
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

项目摘要

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）：这是一项建议，旨在鉴定阿拉吉尔综合征患者（AGS）AGS患者肝病严重程度的临床相关修饰符是一种常染色体显性剂，多系统，可变表达的疾病，是由两个Notch信号通路基因之一突变引起的。在95％的患者中发现JAGGED1（JAG1）中的突变，Notch2的突变小于1％。 AGS引起与肝脏，心脏，肾脏和血管畸形相关的明显发病率。 AG中的肝病在病理学上以肝内胆管缺乏症来表征，导致胆汁淤积，范围从非常温和的（仅具有肝酶的生化异常）到严重的范围，在这种情况下，肝脏损害是广泛的，需要肝脏损害，并且需要一个移植。由于肝病而导致的死亡率约为5％。高度可变的表达性与有助于表达性的修改因素的存在一致。我们假设存在肝病严重程度的遗传修饰符。我们提出了一种多管齐下的方法来识别这些遗传修饰符。使用我们特征良好的AGS和JAG1突变患者的群体，我们将比较轻度肝病的患者与严重的肝病患者，以寻找两组基因组差异的证据。认识到为拟议的研究获得足够的能力的重要性，我们将积极招募其他患者。我们将使用多种技术来寻找轻度肝病患者与严重肝病患者之间的遗传差异。我们将测试拷贝数变体与肝病严重程度的关联。我们将在特定基因组区域（候选基因）中使用随机TAGSNP和SNP进行全基因组关联研究。我们预计，鉴定肝病严重程度的修饰因子将在阿拉吉尔综合征患者之外产生影响，并且可能指出与胆汁淤积有关的其他疾病中肝病严重程度的修饰。