Genetic Epidemiology of Multiple Sclerosis

描述（由申请人提供）：多发性硬化症（MS）是一种使人衰弱的神经免疫和神经退行性疾病，在美国影响超过400，000人。髓鞘丢失、神经胶质增生和不同程度的轴突病理学最终导致进行性神经功能障碍，包括感觉丧失、虚弱、视力丧失、眩晕、不协调、括约肌紊乱和认知改变。遗传因素对多发性硬化症的影响的证据是压倒性的，但病因不是来自单一的主要基因，而是来自多个独立或相互作用的基因。这种复杂性使得寻找负责的遗传变异变得困难。候选基因的方法确定了等位基因与HLA-DR 2等位基因的关联，但没有其他等位基因的关联已得到证实。在当前的资助周期中，我们完成了第二代基因组筛查，初步随访发现了一个与其他研究一致的强染色体连锁信号。我们还产生了令人兴奋的数据，表明MS临床症状的表达受到染色体19 q13上APOE或其附近基因组变异的影响。随着人类基因组计划数据的爆炸，实验室和统计遗传分析的新方法，以及我们MS数据集的大幅扩展，我们现在可以采取新的方法来解剖MS的复杂遗传学。为了实现这些目标，我们提出了五个具体目标（1）：详细检查染色体1 q42以确定潜在的MS风险消失;（2）：分析APOE中和附近的SNP与MS疾病表达的等位基因相关性;（3）：检测MS与氧化应激相关基因之间的相关性;（4）：检查通过MS组织中的表达分析鉴定的基因，并在关键途径中发挥作用;（5）：检测基因-基因相互作用。所有分析都将考虑到我们的高加索人和非洲裔美国人数据集中所见的与HLA-DR 2等位基因的已知关联。我们将对超过200个多重家庭、1,500个美国白人单胎家庭、1,000个英国白人单胎家庭、1,000个对照和1,000个非洲裔美国人单胎家庭进行基因分型。

DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder affecting over 400,000 individuals in the United States. Myelin loss, gliosis, and varying degrees of axonal pathology culminate in progressive neurological dysfunction including sensory loss, weakness, visual loss, vertigo, incoordination, sphincter disturbances, and altered cognition. The evidence for a genetic influence in MS is overwhelming but the etiology springs not from a single major gene, but from multiple genes acting either independently or interactively. This complexity has made the search for the responsible genetic variations difficult. A candidate gene approach identified allelic association with the HLA-DR2 allele but no other allelic associations have been confirmed. In the current funding cycle we completed a second-generation genomic screen and initial follow-up has identified one strong chromosomal linkage signal congruent with other studies. We also generated exciting data suggesting that the expression of clinical symptoms of MS is influenced by genomic variation(s) in or near APOE on chromosome 19q13. With the explosion of data from the human genome project, new methods of laboratory and statistical genetic analysis, and substantial expansion of our MS dataset, we can now take new approaches toward dissecting the complex genetics of MS. To achieve these goals, we propose five specific aims (1): To examine in detail chromosome 1q42 to identify the underlying MS risk gone; (2): To analyze SNPs in and near APOE for allelic associations to MS disease expression; (3): To test for association between MS and genes involved in oxidative stress; (4): To examine genes identified through expression analysis in MS tissues and acting in critical pathways; and (5): To test for gene-gene interactions. All analyses will take into account the known association with the HLA-DR2 allele seen in both our Caucasian and African-American datasets. We will genotype over 200 multiplex families, 1,500 Caucasian US singleton families, 1,000 Caucasian UK singleton families, 1,000 controls, and 1,000 African-American singleton families.