Genetic loci predisposing to multiple sclerosis (MS)

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统慢性神经系统疾病，其特征为多灶性炎症、脱髓鞘和轴突损伤。在CNS的MRI分析中，疾病过程显示炎症导致多个脱髓鞘斑块。MS在疾病的严重程度和进展方面显示出高度的个体差异性。MS的诊断仍然主要基于特征性的临床症状。MS没有特定的实验室检查。然而，MRI的变化和脑脊液中寡克隆IgG条带的存在被用作临床诊断的支持结果。尽管有广泛的研究，MS的发生和发展的基本分子事件仍然知之甚少。大多数MS病例是散发的，但家庭双胞胎和收养研究表明，在MS病例中有很强的遗传成分。 疾病的发病机制。与大多数复杂疾病一样，遗传因素虽然重要，但绝不是唯一的决定因素，环境因素（迄今尚未确定）也是致病因素。由于MS中明显的遗传贡献，我们假设不同的等位基因变异易患MS。我们进一步假设， 因此，我们的目标是鉴定易患MS的基因变异。我们将集中于遗传基因座，我们以前在全基因组扫描中鉴定过，现在仅限于几个兆碱基。我们的策略是利用芬兰MS家庭的独特，种族同质的人口样本。具体而言，我们的目标是：1） 通过监测MS等位基因中的关联和连锁不平衡来限制与MS连锁的染色体基因座，所述MS等位基因使用染色体-5和-17上的关键区域中的多个单核苷酸多态性; 5和-17中选择的候选基因的序列;和 目的1和2检测导致MS的等位基因变体，并在来自更异质人群的研究样本中检测这些等位基因变体。

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.