Molecular Genetics of HLA and Disease

描述(由申请人提供)：本申请的目标是鉴定和表征在MHC区域编码的、易患和/或调节自身免疫性疾病表达的完整基因谱系。在最近由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的扩展该领域跨学科科学的RFA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，以有意义和果断的方式解决这一问题。IMAGEN的研究人员代表了一支由八个学术中心的科学家组成的大型、多样化和基础广泛的合作团队，他们拥有协同技能；在MHC遗传学和生物学方面表现出的专业知识；在鉴定内表型方面的临床专业知识；相互生产性合作的历史；以及大规模基因分型和最先进的分析方法方面的经验。这一合作项目的基本结构提出了一个共同的基础筛查，其中包括1500多个高度信息量的SNP和针对所有疾病的复制。生物学上相关的临床终点将被纳入分析，以评估人类白细胞抗原变异在进展中的作用。每个项目的具体目标3将涉及疾病具体问题。主屏幕将允许我们：1)将关联信号(S)映射到整个MHC以确定最大信号的区域；2)识别携带最强关联信号的扩展MHC单倍型；3)识别最大限度地限定关联的重组染色体；4)做出可测试的假设，关于不同的自身免疫性疾病是受到与特定基因座的单个关联的影响，还是与扩展单倍型的单个关联或跨MHC的多个独立关联的影响。重点关注多发性硬化、类风湿性关节炎、IgA缺陷、常见变量免疫缺陷、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。加州大学旧金山分校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类型的生成、数据质量控制、存储以及与BISC的交互。

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.