Genetic Susceptibility to Biliary Atresia

胆道闭锁的遗传易感性

• 批准号: 8909122
• 负责人: Marcella Devoto
• 金额: $ 66.62万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909122
• 关键词: Accounting; Address; Affect; Ancillary Study; Area; Biliary Atresia; Biliary cirrhosis; Bioinformatics; Child; Childhood; Clinical Research; Complex; Copy Number Polymorphism; DNA; Development; Diagnostic; Disease; Disease susceptibility; Dizygotic Twins; Education; Ethnic Origin; Etiology; Extrahepatic; Family; Frequencies; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomic Segment; Genomics; Genotype; Grant; Inflammatory; Knowledge; Lead; Liver diseases; Methodology; Mission; National Institute of Diabetes and Digestive and Kidney Diseases; Parents; Pathogenesis; Pathway interactions; Patients; Population Control; Predisposition; Procedures; Race; Research; Resources; Sampling; Siblings; Single Nucleotide Polymorphism; Susceptibility Gene; Testing; Therapeutic; Twin Multiple Birth; Variant; Work; base; biliary tract; case control; clinical phenotype; cohort; density; effective therapy; exome sequencing; follow-up; genetic variant; genome wide association study; infancy; interest; liver transplantation; medical complication; next generation sequencing; research study

DESCRIPTION (provided by applicant): This is a proposal to identify genetic susceptibility factors for biliary atresia (BA). BA is a devastating pediatric disease associated with medical complications related to a rapidly developing biliary cirrhosis that accounts for 50% of all pediatric liver transplantations. The etiology of BA is unknown, although it is proposed to be multi-factorial, with potential infectious, environmental, inflammatory and genetic causes. In the proposed study, we will test the hypothesis that there is an underlying genetic susceptibility to BA. We will identify susceptibility genes for BA using a large, well-characterized cohort of patients that has been identified through an NIDDK sponsored research consortium. We will conduct a genome-wide association study, testing for association of genetic variation (both single nucleotide polymorphisms and copy number variants) to identify genes or genomic regions associated with BA disease susceptibility. We will perform exome sequencing of a family with two affected and one unaffected sibling, and three additional unrelated BA patients. We will follow up on regions and genes identified, via next generation sequencing to identify causal variants. This proposal will build upon the resources of a large multi-center consortium and our own cutting-edge genomic and bioinformatic facilities. We anticipate that our studies will contribute new knowledge about the biologic pathogenesis of BA and will lead to the development of rationale therapeutics and diagnostics.

描述（由申请方提供）：这是一项旨在确定胆道闭锁（BA）遗传易感因素的提案。BA是一种毁灭性的儿科疾病，与快速发展的胆汁性肝硬化相关的医疗并发症有关，占所有儿科肝移植的50%。BA的病因尚不清楚，尽管它被认为是多因素的，具有潜在的感染、环境、炎症和遗传原因。在拟议的研究中，我们将测试的假设，有一个潜在的遗传易感性BA。我们将使用通过NIDDK赞助的研究联盟确定的大量特征良好的患者队列来识别BA的易感基因。我们将进行全基因组关联研究，检测遗传变异（单核苷酸多态性和拷贝数变异）的关联，以确定与BA疾病易感性相关的基因或基因组区域。我们将对一个有两个受影响的兄弟姐妹和一个未受影响的兄弟姐妹以及另外三个无关的BA患者的家庭进行外显子组测序。我们将通过下一代测序来跟踪确定的区域和基因，以确定致病变异。该提案将建立在一个大型多中心联盟的资源和我们自己的尖端基因组和生物信息学设施的基础上。我们期望我们的研究将有助于对BA的生物学发病机制的新知识，并将导致合理的治疗和诊断的发展。