Immunogenetic Studies in Multiple Sclerosis

描述（由申请人提供）：多发性硬化（MS）是一种常见的中枢神经系统炎症性疾病，其特征在于包括强遗传成分的复杂病因。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饰基因组决定因素。基于MS包括一个以上的基本表型的假设，和理解，基因组不平衡的模式是由人口历史形成的，我们提出了对比种族群体的研究，以确定早期重组事件和最小的基因组区域窝藏疾病基因。 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MS患者。具体目标1描述了一个全基因组关联筛选的中等分辨率（约6,000微卫星标记），使用高效的DNA池的方法。具体目标2主要涉及候选染色体区域6p 21和19 q13的详细分析。在特定目标3中，将直接检测有希望的候选基因的突变和与疾病易感性相关的信息多态性。临床和副临床变量将按基因型分层，以解决MS异质性问题以及不同表型和基因型之间的相关性。 这些研究成功的关键将是获得大量信息丰富的数据集，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，充分的生物信息学工具和创新的分析策略的可用性。

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.