Genetic loci predisposing to multiple sclerosis (MS)

易患多发性硬化症 (MS) 的基因位点

• 批准号: 6665076
• 负责人: LEENA PELTONEN
• 金额: $ 25.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665076
• 关键词: Scandinavian; clinical research; family genetics; gene expression; genetic disorder diagnosis; genetic polymorphism; genetic screening; genetic susceptibility; genome; human subject; linkage disequilibriums; multiple sclerosis; myelinopathy; neurogenetics

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.

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统的慢性神经系统疾病，其特征为多灶性炎症、脱髓鞘和轴突损伤。在中枢神经系统 MRI 分析中，疾病过程显示炎症导致多处脱髓鞘斑块。 MS 在疾病的严重程度和进展方面表现出高度的个体差异。 MS的诊断仍主要根据特征性临床症状。没有针对多发性硬化症的具体实验室测试。然而，MRI 的变化和脑脊液中寡克隆 IgG 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，但对多发性硬化症发生和进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都是散发性的，但家庭双胞胎和收养研究表明，多发性硬化症有很强的遗传因素。 该疾病的发病机制。与大多数复杂疾病一样，遗传因素虽然很重要，但绝不是唯一的决定因素，但迄今为止尚未确定的环境因素对发病机制有所贡献。由于多发性硬化症中明显的遗传因素，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，特征良好， 种族同质群体在识别易导致复杂性状（例如多发性硬化症）的遗传变异方面具有优势。因此，我们的目标是识别易患多发性硬化症的基因变异。我们将重点关注基因位点，这些基因位点是我们之前在全基因组扫描中发现的，现在仅限于几个兆碱基。我们的策略是利用芬兰多发性硬化症家庭独特的、种族同质的人口样本。更具体地说，我们的目标是：1) 使用 5 号和 -17 号染色体关键区域的多个单核苷酸多态性监测 MS 等位基因中的关联和连锁不平衡，限制与 MS 相关的染色体位点； 2) 使用表达微阵列监测位于Chr.-5和-17关键区域的基因的差异表达； 3) 序列中选择的候选基因 目标 1 和 2 检测导致 MS 的等位基因变异，并在来自更多异质人群的研究样本中测试这些等位基因变异。