Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis
Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis
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DOI：
10.1038/gene.2009.82
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发表时间：
2010-03-01
影响因子：
5
通讯作者：
Olsson, T.
中科院分区：
文献类型：
--
作者：
Ockinger, J.;Stridh, P.;Olsson, T.
多发性硬化症（MS）是一种复杂的中枢神经系统疾病，可引起炎症、脱髓鞘和轴突损伤。MS的遗传风险因素数量有限，但该病的病因仍在很大程度上未知。为了鉴定调节神经炎症的基因，我们使用了MS大鼠模型，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），并进行了连锁分析，在先进的互交系（AIL）。因此，我们重新定义Eae 18 b基因座的0.88Mb的区域，包括一个集群的趋化因子基因。此外，我们显示差异表达的Ccl 2，Ccl 11和Ccl 11在EAE大鼠品系相反的易感性EAE，Eae 18 b基因型调控。在来自四个北欧国家的3841例病例和4046例对照中检测了人类同源基因与MS的相关性。CCL 2中的单倍型和CCL 1中的rs3136682显示与MS的保护性关联，而CCL 13中的单倍型是疾病易感的。在HLA-DRB 1 *15阳性亚组中，我们还确定了与CCL 2中的风险单倍型的关联，这表明了人类白细胞抗原（HLA）基因座的影响。我们进一步确定了CCL 2、CCL 8和CCL 13与类风湿性关节炎的相关性，表明了复杂疾病的共同调控机制。Genes and Immunity（2010）11，142-154; doi：10.1038/gene.2009.82; 2009年10月29日在线发表
Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88Mb region, including a cluster of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries. A haplotype in CCL2 and rs3136682 in CCL1 show a protective association to MS, whereas a haplotype in CCL13 is disease predisposing. In the HLA-DRB1*15 positive subgroup, we also identified an association to a risk haplotype in CCL2, suggesting an influence from the human leukocyte antigen (HLA) locus. We further identified association to rheumatoid arthritis in CCL2, CCL8 and CCL13, indicating common regulatory mechanisms for complex diseases. Genes and Immunity (2010) 11, 142-154; doi: 10.1038/gene.2009.82; published online 29 October 2009