ABSTRACT
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.
Subject(s)
Arthritis, Rheumatoid/genetics , Chemokines, CC/genetics , Encephalomyelitis, Autoimmune, Experimental/genetics , Multiple Sclerosis/genetics , Animals , Central Nervous System/immunology , Chemokines/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Genetic Linkage , Genotype , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Humans , Mice , Myelin Proteins , Myelin-Associated Glycoprotein/genetics , Myelin-Associated Glycoprotein/immunology , Myelin-Oligodendrocyte Glycoprotein , RatsABSTRACT
Multiple sclerosis (MS) is a chronic neurological disease affecting the central nervous system (CNS). The disease is characterised by demyelination and axonal loss caused by abnormal immunological responses resulting in accumulating neurological disabilities. MS is considered a complex disease, with both genetic and environmental factors contributing to the pathogenesis. In this study, we have investigated the genetic role of the myeloperoxidase (MPO) gene encoding myeloperoxidase in MS. MPO is an enzyme found in myeloid cells which catalyses the production of hypochlorus acid, a potent microbicidal agent. It also plays an important role in inflammatory processes, where migrating neutrophiles may release active MPO and cause tissue damage. In this study, we investigated two polymorphisms located in the promotor region of the MPO gene, known to influence the expression of MPO, in a large case/control material consisting of 871 Swedish MS patients and 532 Swedish healthy controls. No association was observed with risk of MS.
