Genetic loci predisposing to multiple sclerosis (MS)

描述(申请人提供)：多发性硬化症(MS)是一种以多灶性炎症、脱髓鞘和轴突损伤为特征的慢性中枢神经系统疾病。在中枢神经系统的MRI分析中，疾病过程显示炎症导致多个斑块脱髓鞘。多发性硬化症显示疾病的严重程度和进展具有高度的个体差异性。多发性硬化症的诊断仍以典型的临床症状为主。目前尚无针对MS的特异性实验室检查，但MRI改变和脑脊液中有寡克隆抗体条带的存在可作为临床诊断的依据。尽管有广泛的研究，但对多发性硬化症发生和发展中的基本分子事件仍知之甚少。大多数多发性硬化症病例是散发性的，但双胞胎家庭和收养研究表明，多发性硬化症的遗传成分很强 疾病的发病机制。正如在大多数复杂疾病中一样，遗传因素虽然重要，但绝不是唯一的决定因素，但环境因素迄今尚未确定，它们对发病起到了作用。由于多发性硬化症的明显遗传贡献，我们假设不同的等位基因变异易患多发性硬化症。我们进一步假设， 种族同质性群体在鉴定易患复杂性状的遗传变异方面具有优势，例如MS。因此，我们的目标是鉴定易患MS的基因变异。我们将重点研究遗传基因座，我们以前在全基因组扫描中发现了这些基因座，现在仅限于几个百万碱基。我们的战略是利用芬兰多发性硬化症家庭中独特的、种族同质的人口样本。更具体地，我们的目标是：1) 通过在染色体-5和-17上的关键区域使用多个单核苷酸多态来监测MS等位基因中的关联和连锁不平衡来限制与MS链接的染色体座位；2)使用表达芯片监测位于Chr.-5和-17关键区域上的基因的差异表达；以及3)在MS等位基因中选择 目标1和2检测导致多发性硬化症的等位基因变异，并在来自更多异质群体的研究样本中测试这些等位变异。

DESCRIPTION (provided by the applicant): Multiple Sclerosis (MS) is a chronic neurological disease of the central nervous system characterized by multifocal inflammation, demyelination and axonal damage. The disease process shows inflammation resulting in multiple patches of demyelination in MRI analyses of CNS. MS shows a high-degree of individual variability in the severity and progress of the disease. The diagnosis of MS is still mainly based on the characteristic clinical symptoms. There are no specific laboratory tests for MS. However, changes in MRI and presence of oligoclonal IgG bands in the cerebrospinal fluid are used as supporting findings for the clinical diagnosis. In spite of extensive research, the basic molecular events in the initiation and progression of MS are still poorly understood. Most MS cases are sporadic, but family twin and adoption studies indicate a strong genetic component in the pathogenesis of the disease. As in most complex diseases, the genetic contribution, although important, is by no means the sole determinant, but environmental, so far unidentified, factors contribute to the pathogenesis. Due to the evident genetic contribution in MS, we hypothesize that distinct allelic variations predispose to MS. We further hypothesize that well-characterized, ethnically-homogenous populations provide advantages in identification of genetic variations predisposing to complex traits, such as MS. Thus, we aim to identify gene variants predisposing to MS. We will focus on genetic loci, which we have previously identified in a genome-wide scan and now restricted to a few megabases. Our strategy is to utilize the unique, ethnically homogenous population sample of Finnish MS families. More specifically, we aim to: 1) Restrict chromosomal loci linked to MS by monitoring for association and linkage disequilibrium, in MS alleles using multiple single nucleotide polymorphisms in the critical regions on chromosomes-5 and -17; 2) monitor differential expression of genes located on the critical region of Chr.-5 and -17 using expression microarrays; and 3) sequence candidate genes selected in Aims 1 and 2 to detect allelic variants contributing to MS, and test these allelic variants in a study sample from more heterogeneous populations.