Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden.
Genes Immun. 2010 Jun;11(4):279-93. doi: 10.1038/gene.2009.111. Epub 2010 Jan 14.
Rat chromosome 1 harbors overlapping quantitative trait loci (QTL) for cytokine production and experimental models of inflammatory diseases. We fine-dissected this region that regulated cytokine production, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), anti-MOG antibodies and pristane-induced arthritis (PIA) in advanced intercross lines (AILs). Analysis in the tenth and twelfth generation of AILs resolved the region in two narrow QTL, Eae30 and Eae31. Eae30 showed linkage to MOG-EAE, anti-MOG antibodies and levels of interleukin-6 (IL-6). Eae31 showed linkage to EAE, PIA, anti-MOG antibodies and levels of tumor necrosis factor (TNF) and IL-6. Confidence intervals defined a limited set of potential candidate genes, with the most interesting being RGMA, IL21R and IL4R. We tested the association with multiple sclerosis (MS) in a Nordic case-control material. A single nucleotide polymorphism in RGMA associated with MS in males (odds ratio (OR)=1.33). Polymorphisms of RGMA also correlated with changes in the expression of interferon-gamma (IFN-gamma) and TNF in cerebrospinal fluid of MS patients. In IL21R, there was one positively associated (OR=1.14) and two protective (OR=0.87 and 0.68) haplotypes. One of the protective haplotypes correlated to lower IFN-gamma expression in peripheral blood mononuclear cells of MS patients. We conclude that RGMA and IL21R and their pathways are crucial in MS pathogenesis and warrant further studies as potential biomarkers and therapeutic targets.
大鼠染色体 1 上存在细胞因子产生的重叠数量性状位点 (QTL) 和炎症性疾病的实验模型。我们精细剖析了这个调节细胞因子产生、髓鞘少突胶质细胞糖蛋白 (MOG)-诱导的实验性自身免疫性脑脊髓炎 (EAE)、抗 MOG 抗体和 pristane 诱导的关节炎 (PIA) 的区域，该区域位于高级互交系 (AILs) 中。在 AIL 的第十和第十二代中进行的分析将该区域解析为两个狭窄的 QTL，Eae30 和 Eae31。Eae30 与 MOG-EAE、抗 MOG 抗体和白细胞介素-6 (IL-6) 水平相关联。Eae31 与 EAE、PIA、抗 MOG 抗体和肿瘤坏死因子 (TNF) 和 IL-6 水平相关联。置信区间定义了一组有限的潜在候选基因，其中最有趣的是 RGMA、IL21R 和 IL4R。我们在北欧病例对照材料中测试了与多发性硬化症 (MS) 的关联。RGMA 中的一个单核苷酸多态性与男性 MS 相关 (比值比 (OR)=1.33)。RGMA 的多态性也与 MS 患者脑脊液中干扰素-γ (IFN-gamma) 和 TNF 的表达变化相关。在 IL21R 中，有一个正相关 (OR=1.14) 和两个保护性 (OR=0.87 和 0.68) 单倍型。其中一个保护性单倍型与 MS 患者外周血单个核细胞中 IFN-gamma 表达降低相关。我们得出结论，RGMA 和 IL21R 及其途径在 MS 发病机制中至关重要，值得进一步研究作为潜在的生物标志物和治疗靶点。
