Immunogenetic Studies in Multiple Sclerosis

多发性硬化症的免疫遗传学研究

• 批准号: 6884631
• 负责人: Jorge R. Oksenberg
• 金额: $ 34.76万
• 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 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6884631
• 关键词: African American; clinical research; computer assisted sequence analysis; computer program /software; data collection methodology /evaluation; disease /disorder onset; family genetics; functional /structural genomics; gene mutation; genetic polymorphism; genetic recombination; genetic screening; genetic susceptibility; genotype; histocompatibility typing; human subject; immunogenetics; linkage disequilibriums; major histocompatibility complex; molecular cloning; multiple sclerosis; patient oriented research; phenotype; statistics /biometry; African American; clinical research; computer assisted sequence analysis; computer program /software; data collection methodology /evaluation; disease /disorder onset; family genetics; functional /structural genomics; gene mutation; genetic polymorphism; genetic recombination; genetic screening; genetic susceptibility; genotype; histocompatibility typing; human subject; immunogenetics; linkage disequilibriums; major histocompatibility complex; molecular cloning; multiple sclerosis; patient oriented research; phenotype; statistics /biometry

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a common inflammatory disorder of the central nervous system characterized by a complex etiology that includes a strong genetic component. Our goal is to integrate modern statistical and molecular genomic methods to identify susceptibility and modifier genomic determinants in this disease. Based on the hypothesis that MS encompasses more than one basic phenotype, and the understanding that patterns of genomic dysequilibrium are shaped by the population history, we propose the study of contrasting ethnic groups to identify early recombination events and minimal genomic regions harboring disease genes. We will use rigorous clinical criteria to ascertain 1000 MS patients of African-American descent. Specific Aim 1 describes a whole genome association screen of medium resolution (approximately 6,000 microsatellite markers) using a highly effective DNA pooling approach. Specific Aim 2 is primarily concerned with the detailed analysis of the candidate chromosomal regions 6p21 and 19q13. In Specific Aim 3, promising candidate genes will be directly tested for mutations and informative polymorphisms associated with disease susceptibility. Clinical and paraclinical variables will be stratified by genotypes to address the question of heterogeneity in MS and the correlation between different phenotypes and genotypes. Key to the success of these studies will be the acquisition of a large and informative dataset, together with the standardization of rigorous and consistent methods to collect relevant clinical data, and availability of efficient genotyping methods, adequate bioinformatic tools, and innovative analytical strategies.

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炎症性疾病，其特征是复杂的病因，其中包括强大的遗传成分。我们的目标是整合现代统计和分子基因组方法，以鉴定该疾病中的敏感性和修饰剂基因组决定因素。基于MS包含多种基本表型的假设，并且理解基因组染色体的模式是人口史所塑造的，我们提出了对比族裔群体的研究，以鉴定早期重组事件和最小的基因组区域，含有疾病基因。 我们将使用严格的临床标准来确定1000毫秒非裔美国人血统的患者。特定的目标1使用高效的DNA聚合方法描述了中等分辨率（约6,000个微卫星标记）的整个基因组关联屏幕。具体目标2主要涉及对候选染色体区域6p21和19q13的详细分析。在特定的目标3中，有前途的候选基因将直接测试与疾病易感性相关的突变和信息性多态性。基因型将通过基因型分层临床和层流变量，以解决MS中异质性的问题以及不同表型与基因型之间的相关性。 这些研究成功的关键将是获取大型且内容丰富的数据集，以及严格且一致的方法的标准化，以收集相关的临床数据，以及有效的基因分型方法的可用性，适当的生物信息学工具以及创新的分析策略。