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; 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（由申请人提供）：多发性硬化症（MS）是中枢神经系统的常见和严重疾病，其特征是慢性炎症，髓磷脂丧失，胶质病，轴突差异不同，轴突和少突胶质细胞病理学以及进行性神经功能障碍。 MS发病机理包括一个复杂的遗传成分。尽管许多研究小组进行了大量的长期努力，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感MS并调节其表现的基因的曲目。现在，由于在定义遗传组织的景观和人类基因组的分类差异方面的快速进步，它们的鉴定是可能的。我们使用严格的临床标准来确定2000毫秒患者并匹配非裔美国人血统的对照。与美国白人相比，非裔美国人的人口被认为处于中等风险，也许反映出MS在非洲人人口实际上实际上不存在。基于以下假设：遗传异质性是MS固有的，并且理解是，基因组不平衡的模式是由每个人群的历史所塑造的，我们提出了对具有MS的非洲裔美国人的全面遗传研究，以鉴定重组事件和最小的基因组地区具有疾病基因的基因组。具体目标1将检验以下假设：HLA级I对独立于II类基因的易感性产生影响，并测试与HLA和KIR等位基因组合相关的证据。特定目标2描述了较大的高分辨率全基因组关联屏幕，以及一种多分析方法，用于从序列和拷贝数多态性中绘制明确的关联信号，从而导致可检验的假设，即具有特定的等位基因变体赋予了易感性。特定目标3利用了非裔美国人MS患者的独特临床特征，并提出了对表型变量及其与基因变异的关系的详细分析。该目标直接解决了MS中临床异质性的问题以及不同表型与基因型之间的相关性。独特，大型且特征良好的数据集的可用性为映射MS相关基因提供了前所未有的机会。此外，与精确评估混合物有关的非裔美国人控制中产生的全基因组数据将为科学界提供重要资源。公共卫生相关性：多发性硬化症（MS）是人类原型脱髓鞘疾病，是成年早期至中期引起神经功能障碍的常见原因。目前尚无治疗疗法，大约90％的受苦个体最终被残疾。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，社会隔离的风险很高。我们的目的是绘制该代码为MS发病机理的产品的基因。我们预计MS可能涉及几个基因。这些基因可能独立或共同起作用，并与环境因素一致影响敏感性。遗传遗传变异的特定组合也可能决定何时出现症状或疾病的发展方式。他们的识别将有助于定义MS的基本病因，改善风险评估并影响治疗剂。