Immunogenetic Studies in Multiple Sclerosis

多发性硬化症的免疫遗传学研究

• 批准号: 7758767
• 负责人: Jorge R. Oksenberg
• 金额: $ 42.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-16 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758767
• 关键词: 6p21.3; Accounting; Address; Admixture; Adult; Affect; African; African American; Age; Alleles; Attention; Autoimmune Diseases; Autoimmunity; Back; Brain; Cataloging; Catalogs; Central Nervous System Diseases; Characteristics; Chromosome Mapping; Chromosomes; Chronic; Clinical; Clinical Course of Disease; Code; Communities; Complex; Copy Number Polymorphism; DNA; Data; Data Set; Demyelinating Diseases; Development; Disabled Persons; Disease; Disease susceptibility; Environmental Risk Factor; Ethnic group; Etiology; European; Event; Funding; Genes; Genetic; Genetic Heterogeneity; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genome; Genomics; Genotype; Gliosis; Goals; Gold; HLA Class I Genes; Haplotypes; Heterogeneity; Human; Human Genome; Immunogenetics; Individual; Inflammation; Inherited; Knowledge; Laboratories; Lesion; Link; Linkage Disequilibrium; MHC Class I Genes; MHC Class II Genes; Maps; Mediating; Methods; Monozygotic twins; Multiple Sclerosis; Myelin; Natural Killer Cells; Neurologic Dysfunctions; Oligodendroglia; Onset of illness; Outcome; Pathogenesis; Pathology; Patients; Pattern; Peptide Signal Sequences; Phenotype; Population; Predisposition; Recording of previous events; Relative Risks; Reporting; Research; Resistance to infection; Resolution; Resources; Risk; Risk Assessment; Role; Shapes; Siblings; Signal Transduction; Social isolation; Specimen; Susceptibility Gene; Symptoms; Testing; Therapeutic; Unemployment; Validation; Variant; Work; aquaporin 4; base; caucasian American; clinical phenotype; cohort; combinatorial; disability; follow-up; genetic analysis; genome wide association study; high risk; improved; interest; novel; public health relevance; receptor; segregation; socioeconomics

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.

描述(申请人提供)：多发性硬化症(MS)是一种常见和严重的中枢神经系统疾病，其特征是慢性炎症、髓鞘丢失、胶质增生、不同程度的轴突和少突胶质细胞病理，以及进行性神经功能障碍。MS的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密集的努力，但对多发性硬化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。由于在确定遗传组织的格局和编目整个人类基因组的变异方面取得了快速进展，它们的鉴定现在成为可能。我们正在使用严格的临床标准来确定2000名多发性硬化症患者和匹配的非裔美国人后裔对照。与美国白人相比，美国非裔美国人被认为处于中等风险，这可能反映了这样一个事实，即非洲土著人口中几乎没有多发性硬化症。基于遗传异质性是多发性硬化症与生俱来的假设，以及对基因组不平衡模式由每个群体的历史所塑造的理解，我们建议对患有多发性硬化症的非裔美国人进行全面的遗传学研究，以确定重组事件和含有疾病基因的最小基因组区域。具体目标1将检验这一假设，即存在独立于II类基因的人类白细胞抗原I类对易感性的影响，并测试与人类白细胞抗原和KIR等位基因组合相关的证据。特殊目的2描述了一个大的高分辨率全基因组关联筛选，以及一种多分析方法来从序列和拷贝数多态映射明确的关联信号，导致关于哪些是与易感性有关的特定等位基因变异的可检验的假设。具体目标3利用非裔美国人多发性硬化症患者的独特临床特征，提出了对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多发性硬化症的临床异质性问题，以及不同表型和基因型之间的相关性。一个独特的、庞大的、具有良好特征的数据集的出现，为绘制MS相关基因图谱提供了前所未有的机会。此外，在非裔美国人对照中产生的与混合的准确评估有关的全基因组数据将为科学界提供重要的资源。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，是导致成年早期至中期神经功能障碍的常见原因。目前尚无根治疗法，约90%的患者最终致残。这种长期疾病的社会经济后果令人震惊，因为75%-85%的患者最终失业，处于社会孤立的高风险中。我们的目标是定位编码MS发病机制相关产物的基因。我们推测多发性硬化症可能涉及多个基因，这些基因可能独立作用，也可能共同作用，与环境因素共同影响易感性。遗传基因变异的特定组合也可能决定症状何时发展，或疾病如何进展。他们的识别将有助于确定MS的基本病因，改进风险评估，并影响治疗。