Immunogenetic Studies in Multiple Sclerosis

项目摘要 多发性硬化症(MS)是一种常见的严重的中枢神经系统疾病 以慢性炎症、髓鞘丢失、胶质增生、不同程度的轴突和 少突胶质细胞病理学和进行性神经功能障碍。多发性硬化发病机制 包括一种复杂的遗传成分。尽管许多人进行了密集的长期努力 研究小组认为，关于多发性硬化症遗传学的知识仍然不完整。我们的总体目标是 描述易患多发性硬化症和调节多发性硬化症的基因谱系。 由于在定义地貌方面取得了快速进展，现在可以识别它们 跨人类基因组的遗传组织和编目变异。 我们正在使用严格的临床标准来确定2000名MS患者和匹配的对照组 非裔美国人后裔。美国非裔美国人的人口被认为处于中等水平 与美国白人相比的风险，可能反映了这样一个事实，即多发性硬化症实际上 在非洲本土人口中不存在。基于这样的假设，即遗传异质性 多发性硬化症固有的，以及对基因组不平衡模式是形成的理解 根据每个种群的历史，我们建议对非洲人进行全面的遗传研究 美国多发性硬化症患者识别重组事件和最小基因组区域 疾病基因。《特定目标1》将检验以下假设：人类白细胞抗原I类对人类免疫缺陷病毒的影响 独立于II类基因的易感性，并测试与 人类白细胞抗原和KIR等位基因的组合。特指目标2描述了一种大型高分辨率 全基因组关联屏幕，以及多分析方法来绘制图谱 来自序列和拷贝数多态的明确关联信号，领先 关于哪些是导致易感性的特定等位基因变异的假设是可检验的。 特殊目标3利用非裔美国人多发性硬化症的独特临床特征 并提出了表型变量的详细分析及其与 基因变异。这一目标直接解决了多发性硬化症和多发性硬化症的临床异质性问题。 不同表型和基因型间的相关性。 唯一、大型且特征良好的数据集的可用性提供了 绘制多发性硬化症相关基因图谱的机会前所未有。此外，生成的整体- 非裔美国人对照中的基因组数据与准确评估混合将 作为科学界的重要资源。

Project Summary Multiple sclerosis (MS) is a common and severe disorder of the central nervous system characterized by chronic inflammation, myelin loss, gliosis, varying degrees of axonal and oligodendrocyte pathology, and progressive neurological dysfunction. MS pathogenesis includes a complex genetic component. In spite of intensive long-standing efforts by many research groups, the knowledge of MS genetics remains incomplete. Our overall objective is to characterize the repertoire of genes that predispose to MS and modulate its presentation. Their identification is now possible as a result of rapid progress in defining the landscape of genetic organization and cataloging variation across the human genome. We are using rigorous clinical criteria to ascertain 2000 MS patients and matched controls of African-American descent. The African American U.S. population is considered at moderate risk when compared to white Americans, perhaps reflecting the fact that MS is virtually absent in native African populations. Based on the hypothesis that genetic heterogeneity is inherent to MS, and the understanding that patterns of genomic disequilibrium are shaped by the history of each population, we propose a comprehensive genetic study of African Americans with MS to identify recombination events and minimal genomic regions harboring disease genes. Specific Aim 1 will test the hypothesis that there is an HLA-class I effect on susceptibility independent from class II genes, and test for evidence of association with combinations of HLA and KIR alleles. Specific Aim 2 describes a large high-resolution genome-wide association screen, together with a multi-analytical approach to map unambiguous association signals from sequence and copy number polymorphisms, leading to testable hypotheses as to which are the specific allelic variants conferring susceptibility. Specific Aim 3 takes advantage of the unique clinical features of African American MS patients and proposes a detailed analysis of phenotypic variables and their relationship to gene variants. This aim directly addresses the question of clinical heterogeneity in MS and the correlation between different phenotypes and genotypes. The availability of a unique, large, and well-characterized dataset provides an unprecedented opportunity to map MS-related genes. In addition, the generated whole- genome data in African American controls linked to precise assessment of admixture will serve as an important resource for the scientific community.