Molecular Genetics of HLA and Disease

HLA 与疾病的分子遗传学

• 批准号: 7110955
• 负责人: STEPHEN L HAUSER
• 金额: $ 182.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110955
• 关键词: autoimmune disorder; clinical research; cooperative study; genetic susceptibility; human subject; major histocompatibility complex; single nucleotide polymorphism

DESCRIPTION (provided by applicant): The goal of this application is to identify and characterize the complete repertoire of genes encoded in the MHC region that predispose and/or modulate the expression of autoimmune disease. Following the recent NINDS-sponsored workshop on MHC Genetics in Autoimmune Diseases and the subsequent announcement of an RFA to extend interdisciplinary science in this area, we created a Consortium, named The International MHC and Autoimmunity Genetics Network (IMAGEN) to tackle this problem in a meaningful and decisive manner. The IMAGEN investigators represent a large, diverse, and broad-based collaborative team of scientists at eight academic centers with synergistic skills; demonstrated expertise in MHC genetics and biology; clinical expertise in identifying endophenotypes; history of mutual productive collaborations; and experience in large scale genotyping and state-of-the-art analytical approaches. The basic structure of this collaborative project proposes a common base screen with a panel of more than1500 highly informative SNPs and replication for all diseases. Biologically relevant clinical endpoints will be incorporated into the analysis to assess the role of HLA variants in progression. Specific aim 3 for each project will address disease-specific questions. The primary screen will allow us to: 1) map the association signal(s) across the entire MHC to identify regions of the maximal signal; 2) identify extended MHC haplotypes carrying the strongest association signals; 3) identify recombinant chromosomes that maximally delimit the association; 4) make testable hypotheses as to whether different autoimmune diseases are influenced by a single association with a particular locus, or a single association with an extended haplotype or multiple, independent associations across the MHC. The focus is on Multiple Sclerosis, Rheumatoid Arthritis, IgA Deficiency, Common Variable Immunodeficiency, Myasthenia Gravis, Systemic Lupus Erythematosus and Ulcerative Colitis. We believe that the clinical dataset assembled for this project is unmatched anywhere in the world. An Administrative Core at UCSF will coordinate activities and interactions for the overall project. A second Core at the Broad Institute will be responsible for generation of genotypes, data QC, storage, and interaction with BISC.

描述（由申请人提供）：本申请的目的是鉴定和表征在MHC区域中编码的基因的完整库，所述基因易患和/或调节自身免疫性疾病的表达。 在最近NINDS赞助的关于自身免疫疾病中MHC遗传学的研讨会以及随后宣布RFA以扩展该领域的跨学科科学之后，我们创建了一个名为国际MHC和自身免疫遗传学网络（IMAGEN）的联盟，以有意义和决定性的方式解决这个问题。IMAGEN研究人员代表了八个学术中心的一个大型，多样化和基础广泛的科学家合作团队，具有协同技能;在MHC遗传学和生物学方面的专业知识;在识别内表型方面的临床专业知识;相互生产合作的历史;以及在大规模基因分型和最先进的分析方法方面的经验。 这个合作项目的基本结构提出了一个共同的基础筛选与一组超过1500个高信息的SNPs和复制的所有疾病。生物学相关临床终点将纳入分析，以评估HLA变体在进展中的作用。每个项目的具体目标3将解决具体疾病问题。初步筛选将允许我们：1）绘制整个MHC上的关联信号以识别最大信号的区域; 2）识别携带最强关联信号的扩展MHC单倍型; 3）识别最大限度地界定关联的重组染色体; 4）做出可检验的假设，以确定不同的自身免疫性疾病是否受到与特定基因座的单一关联的影响，或与扩展单倍型的单一关联或跨MHC的多个独立关联。重点是多发性硬化症、风湿性关节炎、伊加缺乏症、常见变异性免疫缺陷症、重症肌无力、系统性红斑狼疮和溃疡性结肠炎。我们相信，为该项目收集的临床数据集在世界任何地方都是无与伦比的。UCSF的行政核心将协调整个项目的活动和互动。布罗德研究所的第二个核心将负责基因型的生成、数据质量控制、存储以及与BISC的互动。