Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

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 0.88 Mb 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.