Genetic loci predisposing to multiple sclerosis (MS)

描述（由申请人提供）：多发性硬化症（MS）是一种慢性中枢神经系统疾病，以多灶性炎症、脱髓鞘和轴突损伤为特征。在中枢神经系统的MRI分析中，疾病过程显示炎症导致多片脱髓鞘。多发性硬化症在疾病的严重程度和进展方面表现出高度的个体变异性。多发性硬化症的诊断仍主要基于特征性的临床症状。ms没有专门的实验室检查，但MRI的变化和脑脊液中寡克隆IgG条带的存在可作为临床诊断的支持结果。尽管进行了广泛的研究，但MS发生和发展的基本分子事件仍然知之甚少。大多数多发性硬化症病例是散发性的，但家庭双胞胎和收养研究表明，这种疾病有很强的遗传成分

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.