Identification of IBD Susceptibility Genes

描述(申请人提供)：本申请是为了响应RFA DK-06-504，继续炎症性肠病遗传学联合会(IBDGC)和我们作为遗传研究中心(GRC)的角色，以确定导致炎症性肠病(IBD)发病的易感基因为中心目标而提交的。这将通过以下具体目标来实现。具体目标1：需要扩大、开发和管理联合体资源，以提高识别导致IBD发病的遗传变异的能力。这将通过GRC招募更多的IBD病例来实现，重点是早发性、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CD和UC病例。将收集招募受试者的大量临床数据，生物标本(EBV转化的淋巴母细胞系、DMA、血清、全血)将被确定并存储在NIDDK基因库中，供财团、单个GRC和外部研究人员使用。具体目标2：通过各种相辅相成的方法，包括全基因组关联和跟踪全基因组关联结果作为欧洲血统样本的主要方法，查明导致IBD易感性的遗传变异；以及非洲裔美国人和波多黎各样本的比较关联研究和混合连锁不平衡作图，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能力变异的影响、基因途径分析以及基因-基因和基因-环境相互作用，建立IBD的风险模型。随着本提案中概述的扩大的NIDDK基因库，该联盟将能够利用临床亚型、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：本中心将继续领导利用IBD的资源，在19号染色体上的IBD6区域确定IBD易感基因(S)的工作。IBD是一种主要影响年轻人的胃肠道慢性炎症性疾病，其特点是长期患病，需要有效的药物治疗和实质性的手术治疗。IBDGC和GRC的工作将使我们能够识别导致IBD发病的重要易感和疾病修饰基因，这有望：(1)识别疾病风险人群，(2)预测疾病进程，(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基因鉴定和方法学的进展也可能适用于其他复杂的遗传性疾病。

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.