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RGMA and IL21R show association with experimental inflammation and multiple sclerosis

Genes & Immunity volume 11, pages 279–293 (2010)Cite this article

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Abstract

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-γ (IFN-γ) 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-γ 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.

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Acknowledgements

This study was supported by grants from the Swedish Research council; the Swedish foundation for neurologically handicapped (NHR), Bibbi and Nils Jensens Foundation, Montel Williams Foundation, Söderbergs Foundation, the fp 6 EU programs Neuropromise (LSHM-CT-2005-018637 and Euratools (LSHG-CT-2005-019015). The Norwegian part of the study was supported by Norwegian Foundation for Health and Rehabilitation (2004/2/0125) and Odd Fellow MS society, Norway. The Norwegian Bone Marrow Donor Registry is thanked for its collaboration in the establishment of the Norwegian control material.

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Authors and Affiliations

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

    R Nohra, A D Beyeen, M Khademi, E Sundqvist, M T Hedreul, E Wallström, I Kockum, M Jagodic & T Olsson

  2. Department of Biochemistry and Biophysics, Medical Inflammation Research, Karolinska Institutet, Stockholm, Sweden

    J P Guo & J Lorentzen

  3. Danish Multiple Sclerosis Center Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

    F Sellebjerg & A B Oturai

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

    C Smestad & H F Harbo

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

    H F Harbo

  6. Department of Clinical Neuroscience, Division of Neurology, Karolinska Institutet, Stockholm, Sweden

    J Hillert

  7. Department of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    L Alfredsson

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Nohra, R., Beyeen, A., Guo, J. et al. RGMA and IL21R show association with experimental inflammation and multiple sclerosis. Genes Immun 11, 279–293 (2010). https://doi.org/10.1038/gene.2009.111

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