CD24 Polymorphism and multiple sclerosis

描述（由申请人提供）：多发性硬化症（MS）是一种慢性自身免疫性疾病，在白色高加索人中的发病率为1/1000。然而，MS的风险在受影响个体的一级亲属中增加>30倍，在具有受影响的单卵双胞胎的个体中增加约300倍。虽然连锁研究已经暗示了可能影响MS易感性的整个人类基因组中的多个基因座，但HIA-DR基因座仍然是唯一已知的与MS具有一致连锁的基因座。以前的定位研究没有充分考虑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。通过大量的遗传修饰剂，从小鼠遗传研究的见解可能是有价值的，以确定基因和/或其修饰剂。我们最近证明，小鼠CD 24控制实验性自身免疫性脑脊髓炎（EAE），人类多发性硬化症的小鼠模型的发展的关键检查点。此外，由于在CD 24蛋白的关键位置的非保守氨基酸取代，人CD 24基因具有功能多态性。为了检测CD 24的多态性是否是多发性硬化症发病率和临床病程的危险因素，我们使用了700多份多发性硬化症患者和正常对照的血液样本进行了初步研究。我们的研究结果表明，CD 24 v/v的纯合性导致MS的相对风险增加约2。MS和CD 24基因型之间的关联也证实了我们的传输不平衡检验（TDT）。本研究的主要目的是确定CD 24基因多态性对MS发病率和临床病程的贡献，并确定CD 24基因多态性导致MS发病的分子基础。我们的结果将对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.