Immunogenetic Studies in Multiple Sclerosis

描述(申请人提供)：多发性硬化症(MS)是一种常见的中枢神经系统炎症性疾病，其特点是病因复杂，包括强烈的遗传成分。我们的目标是整合现代统计学和分子基因组学方法，以确定这种疾病的易感性和修正基因组决定因素。基于MS包含不止一种基本表型的假设，以及对基因组平衡模式是由种群历史决定的理解，我们建议对不同种族进行研究，以识别早期重组事件和含有疾病基因的最小基因组区域。 我们将使用严格的临床标准来确定1000名非裔美国人后裔的多发性硬化症患者。具体目标1描述了一种使用高效DNA池方法的中等分辨率(约6,000个微卫星标记)的全基因组关联筛选。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。在具体目标3中，有希望的候选基因将直接测试与疾病易感性相关的突变和信息丰富的多态。临床和副临床变量将按基因类型分层，以解决多发性硬化症的异质性问题以及不同表型和基因类型之间的相关性。 这些研究成功的关键将是获得大量和信息丰富的数据集，以及收集相关临床数据的严格和一致方法的标准化，以及有效的基因分型方法、足够的生物信息学工具和创新的分析策略。

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.