Genetic Epidemiology of Multiple Sclerosis

描述(申请人提供)：多发性硬化症(MS)是一种衰弱的神经免疫和神经退行性疾病，在美国影响超过40万人。髓鞘丢失、胶质增生和不同程度的轴突病理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、协调不良、括约肌障碍和认知改变。遗传影响多发性硬化症的证据是压倒性的，但病因不是来自单个主基因，而是来自独立或相互作用的多个基因。这种复杂性使得寻找负责的基因变异变得困难。一种候选基因方法确定了与HLA-DR2等位基因的等位基因关联，但尚未证实其他等位基因关联。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的临床症状的表达受到染色体19q13上APOE或其附近的基因组变异(S)的影响。随着人类基因组计划的数据爆炸，新的实验室和统计遗传分析方法，以及我们的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1q42以确定潜在的MS风险已经消失；(2)：分析APOE及其附近的SNPs与MS疾病表达的等位基因关联；(3)：测试MS与参与氧化应激的基因之间的关联；(4)：检查通过MS组织中的表达分析和关键途径作用的基因；以及(5)：测试基因与基因之间的相互作用。所有的分析都将考虑在我们的高加索人和非裔美国人的数据集中看到的与人类白细胞抗原-DR2等位基因的已知关联。我们将对200多个多胞胎家庭、1500个高加索美国单身家庭、1000个高加索英国单身家庭、1000个对照家庭和1000个非裔美国单身家庭进行基因分型。

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.