Identification of IBD Susceptibility Genes

IBD易感基因的鉴定

• 批准号: 7688644
• 负责人: MARK S. SILVERBERG
• 金额: $ 26.72万
• 依托单位: SINAI HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2012-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688644
• 关键词: 19p; Admixture; Affect; African American; Antibodies; Area; Biological Markers; Candidate Disease Gene; Child; Chromosomes; Chromosomes, Human, Pair 19; Chronic; Classification; Classification Scheme; Clinical; Clinical Data; Clinical Management; Collection; Communication; Complex; Crohn' s disease; Databases; Development; Disease; Disease susceptibility; Doctor of Philosophy; Environmental Exposure; European; Functional disorder; Funding; Future; Gastroenterologist; Gastrointestinal tract structure; Gene-Modified; Genes; Genetic; Genetic Research; Genetic Variation; Genome; Goals; Hereditary Disease; Hospitals; Individual; Inflammatory; Inflammatory Bowel Diseases; International; Lead; Linkage Disequilibrium; Maps; Medical; Modeling; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Operative Surgical Procedures; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Persons; Phenotype; Population; Positioning Attribute; Preventive; Puerto Rican; Quality Control; Recruitment Activity; Research; Research Personnel; Resources; Risk; Role; Sampling; Screening procedure; Selection for Treatments; Serum; Susceptibility Gene; Testing; Therapeutic Intervention; Training; Ulcerative Colitis; Variant; Whole Blood; Work; base; clinical practice; cohort; comparative; disease classification; disorder risk; disorder subtype; early onset; follow-up; gene discovery; gene environment interaction; gene interaction; genome wide association study; improved; lymphoblastoid cell line; novel; organizational structure; programs; repository; response; sample collection

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.

描述（由申请人提供）：本申请是针对 RFA DK-06-504 提交的，旨在继续炎症性肠病遗传学联盟 (IBDGC) 的努力以及我们作为遗传研究中心 (GRC) 的作用，其中心目标是确定有助于炎症性肠病 (IBD) 发病机制的易感基因。这将通过以下具体目标来实现。具体目标 1：需要扩展、开发和管理联盟资源，以增强识别导致 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，重点关注早发、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，并确定生物样本（EBV 转化的淋巴母细胞系、DMA、血清、全血）并将其存储在 NIDDK 遗传学存储库中，供联盟、各个 GRC 和外部研究人员使用。具体目标 2：通过各种补充方法，包括全基因组关联 (GWA) 和对 GWA 结果的跟踪作为欧洲血统样本的主要方法，确定导致 IBD 易感性的遗传变异；通过非裔美国人和波多黎各样本中的混合连锁不平衡进行比较关联研究和绘图，以及非裔美国人样本中的全基因组关联。具体目标 3：通过了解遗传对表型表达性变化的影响、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。通过本提案中概述的扩大的 NIDDK 遗传学知识库，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 将继续领导工作，利用 IBDGC 的资源识别 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，需要有效的药物治疗和大量手术治疗。 IBDGC 和 GRC 的工作将使我们能够识别导致 IBD 发病机制的重要易感基因和疾病修饰基因，这有望：（1）识别有疾病风险的人，（2）预测疾病进程，（3）帮助选择治疗，（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 基因鉴定和方法学方面的进展也可能适用于其他复杂的遗传性疾病。