Yale University IBD Genetics Research Center

描述（由申请人提供）：本研究计划是根据RFA DK-06-504提交的，目的是继续我们作为NIDDK炎症性肠病遗传学联盟（IBDGC）的遗传研究中心（GRC）的角色。本申请将讨论位于耶鲁大学的各个GRC的组成部分。该联盟的中心目标是确定IBD发病机制的易感基因。此计划将参考IBDGC的DCC提案，此GRC提案应与DCC的主申请一起进行评估。第一个资助期的成果是发现IL23R（白细胞介素23受体）是IBD的主要易感基因。在IL23R基因中已经发现了多个关联信号，特别是一个不常见的编码区变体Arg381Gln，它对CD和DC的发展具有高度显著的保护作用。据报道，德系犹太人群体对CD的功能性先天免疫系统变异进行了初步鉴定。初步研究表明toll样受体5停止变异体TLR5-stop对CD具有保护作用。干扰素调节因子5基因IRF5的多态性直接导致剪接变异体的表达，并与狼疮有关，类似地表明与犹太人CD有关。提出了三个具体目标。具体目标1：财团资源的拓展、开发和管理。我们定义了可操作的YUGRC-DCC-IBDGC接口，以确保财团资源的适当优先级，以及IBD病例和对照的招募和表型表征。具体目标2：采用多种方法鉴定导致IBD易感性的遗传变异。建议在未来的犹太CD病例中进行测试TLR5-stop和IRF5变异的复制研究。提出了IL23R基因及其通路的完整表征。对Nod2基因型进行分层的Nod2通路分析可能会提供更好的结果。通过了解遗传对表型表达变异的影响、基因通路分析以及基因-基因（gx G）和基因-环境（gx E）相互作用，建立IBD风险模型。基于生物学和遗传学模型，将对Nod2和IL23R通路上的基因相互作用进行研究。

DESCRIPTION (provided by applicant): This Research Plan is submitted in response to the RFA DK-06-504 for the purposes of continuing our role as a Genetic Research Center (GRC) of the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC). This application will discuss the components of the individual GRC located at Yale University. The central goal of this Consortium is to identify susceptibility genes contributing to the pathogenesis of IBD. This plan will refer to the proposal of the DCC of the IBDGC and this GRC proposal should be evaluated in conjunction with the Master Application of the DCC. The showpiece of the first funding period has been the identification of IL23R (interleukin 23 receptor) as a major susceptibility gene for IBD. Multiple association signals within the IL23R gene have been identified, notably an uncommon coding region variant, Arg381Gln, which confers highly significant protection against the development of CD and DC. Preliminary identification of functional innate immune system variants to CD in Ashkenazi Jewish cohorts is reported. Preliminary studies demonstrate a protective effect of the toll-like receptor 5 stop variant, TLR5-stop against CD. A polymorphism in the interferon regulatory factor 5 gene, IRF5, that directly results in expression of splice variants and has been associated in lupus, similarly demonstrates association to Jewish CD. Three specific aims are proposed. Specific Aim 1: Expansion, Development and Management of Consortium Resources. We define the operational YUGRC-DCC-IBDGC interface that will assure appropriate prioritization of Consortium resources and recruitment and phenotypic characterization of IBD cases and controls. Specific Aim 2: To employ a variety of approaches to identify genetic variation that contributes to IBD susceptibility. Replication studies testing TLR5-stop and IRF5 variants in future, Jewish CD cases are proposed. Complete characterization of the IL23R gene and pathway is proposed. Nod2 pathway analyses stratified on Nod2 genotypes may provide improved power. Specific Aim 3 To build a risk model of IBD through understanding genetic influence on variations in phenotypic expressivity, gene pathway analysis, and gene-gene (G x G) and gene-environmental (G x E) interactions. Well-powered gene-gene interactions along the Nod2 and IL23R pathways will be examined based on biologic and genetic models.