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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：
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
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/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

项目摘要

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.

项目总结