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

Genes & Immunity volume 11, pages 142–154 (2010)Cite this article

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.

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Acknowledgements

We thank Dr Mohsen Khademi and Maria Karlsson for technical assistance and Dr Boel Brynedal for critical review of the paper. We also thank all the patients and volunteers who contributed to this study. All involved hospital staff are thanked for their contribution, in particular the neurologists Tuula Pirttilä (University of Kuopio), Irina Elovaara (University of Tampere) and Mauri Reunanen (University of Oulu) for their efforts in recruiting Finnish MS patients, and Professor Lars Klareskog (Karolinska Institutet) for recruiting patients to the Swedish RA cohort. This work was supported by grants from the Swedish Research Council, EURATools (LSHG-CT-2005-019015), Neuropromise (LSHM-CT-2005-018637), the Swedish Association for Persons with Neurological Disabilities, the Finnish Academy, the Sigrid Juselius Foundation and Helsinki University Central Hospital.

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  1. M Jagodic and T Olsson: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Clinical Neuroscience, Neuroimmunology Unit, Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    J Öckinger, P Stridh, A D Beyeen, I Kockum, M Jagodic & T Olsson

  2. Department of Clinical Neuroscience, MS Research Group, Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    F Lundmark & J Hillert

  3. Department of Medicine, Rheumatology Unit, Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    M Seddighzadeh & L Padyukov

  4. Department of Neurology, Danish Multiple Sclerosis Research Center, Copenhagen University Hospital, Copenhagen, Denmark

    A Oturai & P S Sørensen

  5. Department of Neurology, Oslo University Hospital, Ullevål, Norway

    Å R Lorentzen & E G Celius

  6. Institute of Immunology, Oslo University Hospital, Rikshospitalet, Norway

    Å R Lorentzen

  7. Unit of Public Health Genomics, National Institute for Health and Welfare, Helsinki, Finland

    V Leppä

  8. Institute for Molecular Medicine and Helsinki Biomedical Graduate School, University of Helsinki, Helsinki, Finland

    V Leppä

  9. Central Hospital of Seinäjoki, Seinäjoki, Finland

    K Koivisto

  10. Molecular Neurology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    P J Tienari

  11. Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland

    P J Tienari

  12. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    L Alfredsson

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  1. J Öckinger
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Öckinger, J., Stridh, P., Beyeen, A. et al. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis. Genes Immun 11, 142–154 (2010). https://doi.org/10.1038/gene.2009.82

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