CD24 Polymorphism and multiple sclerosis

描述(申请人提供)：多发性硬化症(MS)是一种慢性自身免疫性疾病，在白人中的发病率为千分之一。然而，在患病个体的一级亲属中，患多发性硬化症的风险增加30倍，在具有受影响的同卵双胞胎的个体中，风险增加约300倍。虽然连锁研究表明人类基因组中的多个基因座可能影响MS的易感性，但HIA-DR基因座仍然是已知的唯一与MS有一致连锁的基因。此外，以前的作图研究没有充分考虑MS的异质性，因此可能遗漏了控制MS严重程度的遗传修饰因子。由于MS基因可能具有低外显性，并且受到大量遗传修饰因子的影响，因此从小鼠遗传学研究中获得的信息可能对识别这些基因和/或它们的修饰因子很有价值。我们最近已经证明，小鼠CD24控制着实验性自身免疫性脑脊髓炎(EAE)的发展的关键检查点，EAE是人类多发性硬化症的小鼠模型。此外，由于CD24蛋白关键位置的非保守氨基酸替换，人类CD24基因具有功能多态。为了验证CD24基因多态性是否是多发性硬化症发病和临床病程的危险因素，我们对多发性硬化症患者和正常对照组的700多份血液样本进行了初步研究。我们的结果表明，CD24v/v纯合子导致MS的相对风险增加约2%。我们的传递不平衡检验(TDT)也证实了MS与CD24基因之间的关联。本研究的主要目的是确定CD24基因多态性在MS发病和临床病程中的作用，以及CD24基因多态性在MS发病机制中的分子基础。我们的研究结果将对MS的诊断和治疗具有重要意义。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic autoimmune disease with an incidence of 1/1000 in white Caucasians. The risk of MS, however, increases by >30 fold among first-degree relatives of an affected individual and approximately 300-fold among individuals with an affected monozygotic twin. While linkage studies have implicated multiple loci throughout the human genome that may affect the susceptibility to MS, the HIA-DR locus remains the only known one with consistent linkage to MS. Moreover, the previous mapping studies have not taken into full account the heterogeneity of MS and may have therefore left out genetic modifiers that control the severity of MS. Since MS genes are likely to have low penetrances and are affected by a large number of genetic modifiers, insight from mouse genetic studies may be valuable to identify the genes and/or their modifiers. We have recently demonstrated that mouse CD24 controls a critical checkpoint for the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. Moreover, the human CD24 gene has a functional polymorphism due to a non-conserved amino acid substitution in a critical position of the CD24 protein. To test whether polymorphism of CD24 is a risk factor for the incidence and clinical course of multiple sclerosis, we have carried out preliminary studies using more than 700 blood samples from multiple sclerosis patients and normal controls. Our results demonstrated that the homozygocity of CD24v/v resulted in an increase of about 2 in the relative risk of MS. The association between MS and CD24 genotype is also substantiated by our transmission-disequilibrium test (TDT). The main goal of this study is to establish the contribution of CD24 polymorphism to the incidence and clinical course of MS and to determine the molecular basis by which the polymorphism of the CD24 gene contributed to the pathogenesis of MS. Our results will have important implications for the diagnosis and treatment of MS.