Neuroimmunology Unit, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Eur J Hum Genet. 2010 Dec;18(12):1349-52. doi: 10.1038/ejhg.2010.113. Epub 2010 Jul 21.
Multiple sclerosis, MS (OMIM No. 126200), is a complex inflammatory disease that is characterized by lesions in the central nervous system. Both genes and other environmental factors influence disease susceptibility. One of the environmental factors that has been implicated in MS and autoimmune disease, such as type 1 diabetes, is vitamin D deficiency, in which patients have lower levels of 25-hydroxyvitamin D3 (25-OHD(3)) in blood than do controls. Previtamin D(3) is produced in the skin, and turned into 25-OHD(3) in the liver. In the kidney, skin and immune cells, 25-OHD(3) is turned into bioactive 1,25(OH)(2)D(3) by the enzyme coded by CYP27B1 (cytochrome P450 family 27 subfamily B peptide 1) on chromosome 12q13.1-3. 1,25(OH)(2)D(3) binds to the vitamin D receptor, expressed in T cells and antigen-presenting cells. 1,25(OH)(2)D(3) has a suppressive role in the adaptive immune system, decreasing T-cell and dendritic cell maturation, proliferation and differentiation, shifting the balance between T-helper 1 (Th1) and Th2 cells in favor of Th2 cells and increasing the suppressive function of regulatory T cells. Rs703842 in the 12q13-14 region was associated with MS in a recent study by the Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). We show associations with three SNPs in this region in our Swedish materials (2158 cases, 1759 controls) rs4646536, rs10877012 and rs10877015 (P=0.01, 0.01 and 3.5 × 10(-3), respectively). We imputed rs703842 SNP and performed a joint analysis with the ANZgene results, reaching a significant association for rs703842 (P=5.1 × 10(-11); odds ratio 0.83; 95% confidence interval 0.79-0.88). Owing to its close association with 25-OHD(3), our results lend further support to the role of vitamin D in MS pathology.
多发性硬化症（多发性硬化症，MS）（OMIM No. 126200）是一种复杂的炎症性疾病，其特征是中枢神经系统出现病变。基因和其他环境因素都会影响疾病的易感性。维生素 D 缺乏症是一种环境因素，与多发性硬化症和自身免疫性疾病（如 1 型糖尿病）有关，患者血液中的 25-羟基维生素 D3（25-OHD3）水平低于对照组。前维生素 D3 在皮肤中产生，并在肝脏中转化为 25-OHD3。在肾脏、皮肤和免疫细胞中，由 CYP27B1（细胞色素 P450 家族 27 亚家族 B 多肽 1）编码的酶将 25-OHD3 转化为生物活性 1,25（OH）（2）D3。1,25（OH）（2）D3 与维生素 D 受体结合，该受体在 T 细胞和抗原呈递细胞中表达。1,25（OH）（2）D3 在适应性免疫系统中具有抑制作用，可降低 T 细胞和树突状细胞的成熟、增殖和分化，使 T 辅助 1（Th1）和 Th2 细胞之间的平衡向 Th2 细胞倾斜，并增加调节性 T 细胞的抑制功能。在澳大利亚和新西兰多发性硬化症遗传学联合会（ANZgene）的一项最近研究中，12q13-14 区域的 Rs703842 与多发性硬化症有关。我们在瑞典材料（2158 例病例，1759 例对照）中发现该区域的三个 SNP 与该疾病相关：rs4646536、rs10877012 和 rs10877015（P=0.01、0.01 和 3.5×10（-3））。我们对 rs703842 SNP 进行了推测，并与 ANZgene 的结果进行了联合分析，结果表明 rs703842 显著相关（P=5.1×10（-11）；比值比 0.83；95%置信区间 0.79-0.88）。由于它与 25-OHD3 密切相关，我们的结果进一步支持了维生素 D 在多发性硬化症发病机制中的作用。
