Immunogenetic Studies in Multiple Sclerosis

多发性硬化症的免疫遗传学研究

• 批准号: 8409799
• 负责人: Jorge R. Oksenberg
• 金额: $ 38.82万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8409799
• 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; receptor; segregation; socioeconomics

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.

项目摘要 多发性硬化症（MS）是一种常见而严重的中枢神经系统疾病 其特征在于慢性炎症、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和进行性神经功能障碍。MS发病机制 包括复杂的遗传成分。尽管许多人作出了长期的努力， 研究小组，MS遗传学的知识仍然不完整。我们的总体目标是 以表征易患MS并调节其呈递的基因库。 由于在确定这些国家的地貌方面取得了迅速进展， 基因组织和人类基因组中的变异编目。 我们正在使用严格的临床标准，以确定2000 MS患者和匹配的对照， 非裔美国人后裔非裔美国人的美国人口被认为是中等 与白色美国人相比， 在非洲土著中是不存在的。基于遗传异质性是 MS固有的，以及对基因组不平衡模式形成的理解， 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。 患有MS的美国人，以确定重组事件和最小基因组区域， 疾病基因具体目标1将检验HLA-I类效应是否影响 独立于II类基因的易感性，并检测与 HLA和KIR等位基因的组合。具体目标2描述了一个大的高分辨率 全基因组关联筛选，以及多分析方法来定位 来自序列和拷贝数多态性的明确关联信号， 关于哪些是赋予易感性的特定等位基因变体的可检验的假设。 Specific Aim 3利用非裔美国人多发性硬化症独特的临床特征 患者，并提出了一个表型变量的详细分析及其关系， 基因变异这一目标直接解决了MS的临床异质性问题， 不同表型和基因型之间的相关性。 一个独特的、大的、特征良好的数据集的可用性提供了一个 这是一个绘制MS相关基因图谱的前所未有的机会。此外，生成的整体- 非洲裔美国人对照组的基因组数据与混合物的精确评估有关， 是科学界的重要资源。

项目成果

When is the absence of evidence, evidence of absence? Use of equivalence-based analyses in genetic epidemiology and a conclusion for the KIF1B rs10492972*C allelic association in multiple sclerosis.

• DOI: 10.1002/gepi.20592
• 发表时间: 2011-09
• 期刊: GENETIC EPIDEMIOLOGY
• 影响因子: 2.1
• 作者: Gourraud, Pierre-Antoine

The killer immunoglobulin-like receptor KIR3DL1 in combination with HLA-Bw4 is protective against multiple sclerosis in African Americans.

• DOI: 10.1038/gene.2016.5
• 发表时间: 2016-04
• 期刊: Genes and immunity
• 影响因子: 5

Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15.

BTNL2 中的截短剪接位点突变与多发性硬化症的关联继发于 HLA-DRB1*15。

• DOI: 10.1093/hmg/ddi436
• 发表时间: 2006
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Traherne,JamesA;Barcellos,LisaF;Sawcer,StephenJ;Compston,Alastair;Ramsay,PatriciaP;Hauser,StephenL;Oksenberg,JorgeR;Trowsdale,John
• 通讯作者: Trowsdale,John

Copy number variation in African Americans.

• DOI: 10.1186/1471-2156-10-15
• 发表时间: 2009-03-24
• 期刊: BMC genetics
• 影响因子: 2.9
• 作者: McElroy JP;Nelson MR;Caillier SJ;Oksenberg JR
• 通讯作者: Oksenberg JR

Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA.

• DOI: 10.1001/archneurol.2008.541
• 发表时间: 2009-02
• 期刊: ARCHIVES OF NEUROLOGY
• 作者: Cree, Bruce A. C.;Reich, David E.;Khan, Omar;De Jager, Philip L.;Nakashima, Ichiro;Takahashi, Toshiyuki;Bar-Or, Amit;Tong, Christine;Hauser, Stephen L.;Oksenberg, Jorge R.
• 通讯作者: Oksenberg, Jorge R.