Identification of IBD Susceptibility Genes

描述（由申请人提供）：本申请是为了响应RFA DK-06-504而提交的，以继续炎症性肠病遗传学协会（IBDGC）的努力和我们作为遗传研究中心（GRC）的角色，其中心目标是确定与炎症性肠病（IBD）发病机制有关的易感基因。这将通过以下具体目标来实现。具体目标1：需要扩大、开发和管理联盟资源，以提高识别导致IBD发病机制的遗传变异的能力。这将通过GRC招募更多IBD病例来实现，重点是早期发病、溃疡性结肠炎（UC）、非裔美国人克罗恩病（CD）和UC以及波多黎各的CD和UC病例。将收集招募的受试者的广泛临床数据，并确定生物标本（ebv转化淋巴母细胞样细胞系、DMA、血清、全血），并将其储存在NIDDK遗传库中，供联盟、个体GRCs和外部研究者使用。具体目标2：通过各种互补方法确定导致IBD易感性的遗传变异，包括全基因组关联（GWA），并将GWA结果作为欧洲祖先样本的主要方法进行随访；通过非裔美国人和波多黎各人样本的混合连锁不平衡来比较关联研究和定位，以及非裔美国人样本的全基因组关联。具体目标3：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-基因和基因-环境相互作用，建立IBD风险模型。有了本提案中概述的扩展的NIDDK遗传资源库，该联盟将能够利用临床亚表型、基因途径、基因-基因和基因-环境相互作用来进一步了解IBD的遗传基础。具体目标4：该GRC将继续领导利用IBDGC资源鉴定19号染色体IBD6区域的IBD易感基因。IBD是一种胃肠道慢性炎症性疾病，主要影响年轻人，其特点是长期患病，需要强有力的药物治疗和大量的手术治疗。IBDGC和GRC的工作将使我们能够识别IBD发病机制中重要的易感基因和疾病修饰基因，这有可能：(1)识别有疾病风险的人，(2)预测疾病病程，(3)帮助选择治疗方法，(4)了解病理生理机制，以便开发新的预防和治疗干预措施。IBD基因鉴定和方法方法的进展也可能适用于其他复杂的遗传疾病。

DESCRIPTION (provided by applicant): This application was submitted in response to RFA DK-06-504 to continue the efforts of the Inflammatory Bowel Disease Genetics Consortium (IBDGC) and our role as a Genetic Research Center (GRC) with the central goal of identifying susceptibility genes contributing to the pathogenesis of inflammatory bowel disease (IBD). This will be accomplished through the following specific aims. Specific Aim 1: Expansion, development and management of Consortium resources is required to enhance the capacity to identify genetic variation contributing to the pathogenesis of IBD. This will be accomplished through GRC recruitment of additional IBD cases with a focus on early onset, ulcerative colitis (UC), African-American Crohn's disease (CD) and UC, and Puerto Rican CD and UC cases. Extensive clinical data will be collected on recruited subjects and biospecimens (EBV-transformed lymphoblastoid cell lines, DMA, serum, whole blood) will be ascertained and stored at the NIDDK Genetics Repository for use by the Consortium, individual GRCs and outside investigators. Specific Aim 2: To identify genetic variation that contributes to IBD susceptibility through a variety of complementary approaches including genome-wide association (GWA) and follow-up of GWA results as the primary approach in European ancestry samples; and comparative association studies and mapping by admixture linkage disequilibrium in African-American and Puerto Rican samples, and genome-wide association in African-American samples. 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 and gene-environmental interactions. With the expanded NIDDK Genetics Repository outlined in this proposal, the Consortium will be in a position to use clinical subphenotypes, gene pathways, gene-gene and gene-environment interactions to further understand the genetic basis of IBD. Specific Aim 4: This GRC will continue to lead efforts to identify the IBD susceptibility gene(s) in the IBD6 region on chromosome 19 using the resources of the IBDGC.IBD is a chronic inflammatory disease of the gastrointestinal tract which primarily affects young people and is characterized by long-term illness and the need for potent medical therapy and substantial surgical therapy. The work of the IBDGC and this GRC will enable us to identify important predisposing and disease modifying genes contributing to the pathogenesis of IBD which has the promise to: (1) identify persons at risk for disease, (2) predict disease course, (3) aid in selection of treatment, (4) understand pathophysiologic mechanisms such that novel preventive and therapeutic interventions can be developed. Advances in IBD gene identification and methodologic approaches may also be applicable to other complex genetic disorders.