Immunogenetic Studies in Multiple Sclerosis

描述（由申请人提供）：多发性硬化（MS）是一种常见且严重的中枢神经系统疾病，其特征为慢性炎症、髓鞘丢失、神经胶质增生、不同程度的轴突和少突胶质细胞病理学以及进行性神经功能障碍。MS发病机制包括复杂的遗传成分。尽管许多研究小组进行了长期的努力，但对MS遗传学的了解仍然不完整。我们的总体目标是表征易患MS并调节其表达的基因库。由于在定义遗传组织和编目人类基因组变异方面的快速进展，它们的识别现在是可能的。我们正在使用严格的临床标准，以确定2000 MS患者和非裔美国人后裔的匹配控制。与白色美国人相比，美国非裔美国人被认为处于中度风险，这可能反映了MS在非洲本土人群中几乎不存在的事实。基于遗传异质性是多发性硬化症固有的假设，以及基因组不平衡模式由每个人群的历史决定的理解，我们提出对患有多发性硬化症的非裔美国人进行全面的遗传研究，以确定重组事件和携带疾病的最小基因组区域基因。具体目标1将检验HLA I类对易感性的影响独立于II类基因的假设，并检验与HLA和KIR等位基因组合相关的证据。具体目标2描述了一个大的高分辨率的全基因组关联屏幕，连同多分析方法，以映射明确的关联信号从序列和拷贝数多态性，导致可检验的假设，这是特定的等位基因变异赋予易感性。具体目标3利用非裔美国MS患者的独特临床特征，并提出了表型变量及其与基因变异的关系的详细分析。这一目标直接解决了MS的临床异质性问题以及不同表型和基因型之间的相关性。一个独特的，大的，和良好的特征数据集的可用性提供了一个前所未有的机会，映射MS相关基因。此外，在非洲裔美国人对照中产生的与混合物的精确评估相关的全基因组数据将成为科学界的重要资源。公共卫生相关性：多发性硬化症（MS）是人类典型的脱髓鞘疾病，是成年早期至中期神经功能障碍的常见原因。目前没有治愈性疗法，大约90%的患者最终残疾。这种长期存在的疾病的社会经济后果是惊人的，因为75-85%的患者最终失业，并处于社会孤立的高风险之中。我们的目标是映射基因编码的产品参与MS发病机制。我们预计，可能有几个基因参与MS。这些基因可能独立或共同作用，并影响与环境因素的易感性。遗传变异的特定组合也可能决定症状何时出现或疾病如何进展。他们的鉴定将有助于确定MS的基本病因，改善风险评估，并影响治疗。

DESCRIPTION (provided by applicant): 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 a an important resource for the scientific community. PUBLIC HEALTH RELEVANCE: Multiple sclerosis (MS), the prototypic demyelinating disease in humans, is a common cause of neurological dysfunction arising from early to middle adulthood. No curative therapy is currently available and approximately 90% of afflicted individuals are ultimately disabled. The socioeconomic consequences of this long-lasting disease are staggering as 75-85% of patients are eventually unemployed and at high risk for social isolation. We aim to map genes that code for products involved in MS pathogenesis. We anticipate that there may be several genes involved in MS. These genes may work independently or together and affect susceptibility in concert with environmental factors. Particular combinations of inherited genetic variations may also determine when symptoms develop, or how the disease progresses. Their identification will help to define the basic etiology of MS, improve risk assessment, and influence therapeutics.