Genetic Susceptibility to Biliary Atresia

描述(由申请人提供)：这是一项确定胆道闭锁(BA)遗传易感因素的建议。BA是一种毁灭性的儿科疾病，与迅速发展的胆汁性肝硬变相关的内科并发症有关，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，具有潜在的感染性、环境性、炎症性和遗传性。在拟议的研究中，我们将检验这一假设，即存在对BA的潜在遗传易感性。我们将使用一个由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，测试遗传变异(单核苷酸多态和拷贝数变异)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名无血缘关系的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确定因果变异，从而跟踪识别出的区域和基因。这项提议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。我们期待我们的研究将为BA的生物学发病机制提供新的知识，并将导致基本治疗学和诊断学的发展。 公共卫生相关性：胆道闭锁(BA)是一种特发性儿童肝病，缺乏有效的治疗方法，占所有儿童肝移植的一半。我们建议进行一项研究，以确定导致BA易感性的遗传因素，该研究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。我们期待我们的研究将为BA的生物学发病机制提供新的知识，并将导致基本治疗学和诊断学的发展。

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. PUBLIC HEALTH RELEVANCE: Biliary Atresia (BA) is an idiopathic pediatric liver disease lacking effective therapies and accounting for half of all pediatric liver transplantations. We propose a study to identify genetic factors contributing to susceptibility to BA that builds 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.