Article Text

other Versions

PDF
Interferon Regulatory Factor 5 (IRF5) Gene Variants are Associated with Multiple Sclerosis in Three Distinct Populations
  1. Gudlaug Kristjansdottir (gudlaug.kristjansdottir{at}medsci.uu.se)
  1. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
    1. Johanna K. Sandling (johanna.sandling{at}medsci.uu.se)
    1. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
      1. Alessandro Bonetti (alessandro.bonetti{at}helsinki.fi)
      1. Department of Neurology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
        1. Izaura M. Roos (izaura.roos{at}ki.se)
        1. Department of Clinical Neuroscience, Division of Neurology, Karolinska Institutet, Stockholm, Sweden
          1. Lili Milani (lili.milani{at}medsci.uu.se)
          1. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
            1. Chuan Wang (wondric{at}gmail.com)
            1. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
              1. Sigrun M. Gustafsdottir (sigrun.gustafsdottir{at}genpat.uu.se)
              1. Rudbeck laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
                1. Snaevar Sigurdsson (snaevar.sigurdsson{at}medsci.uu.se)
                1. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                  1. Anders Lundmark (anders.lundmark{at}medsci.uu.se)
                  1. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
                    1. Pentti J. Tienari (pentti.tienari{at}hus.fi)
                    1. Department of Neurology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
                      1. Keijo Koivisto (keijo.koivisto{at}epshp.fi)
                      1. Central Hospital of Seinäjoki, Seinäjoki, Finland
                        1. Irina Elovaara (irina.elovaara{at}uta.fi)
                        1. Department of Neurology, University of Tampere and Tampere University Hospital, Tampere, Finland
                          1. Tuula Pirttilä (tuula.pirttila{at}uku.fi)
                          1. Department of Neurology and Neuroscience, University of Kuopio and Kuopio University Hospital, Finland
                            1. Mauri Reunanen (mauri.reunanen{at}ppshp.fi)
                            1. Department Neurology, University of Oulu and Oulu University Hospital, Oulu, Finland
                              1. Leena Peltonen (leena.peltonen{at}ktl.fi)
                              1. Department of Molecular Medicine, Biomedicum, National Public Health Institute, Helsinki, Finland
                                1. Janna Saarela (janna.saarela{at}ktl.fi)
                                1. Department of Molecular Medicine, Biomedicum, National Public Health Institute, Helsinki, Finland
                                  1. Jan Hillert (jan.hillert{at}ki.se)
                                  1. Department of Clinical Neuroscience, Division of Neurology, Karolinska Institutet, Stockholm, Sweden
                                    1. Tomas Olsson (tomas.olsson{at}ki.se)
                                    1. Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden
                                      1. Ulf Landegren (ulf.landegren{at}genpat.uu.se)
                                      1. Rudbeck laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
                                        1. Antonio Alcina (pulgoso{at}ipb.csic.es)
                                        1. Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Inv. Cient&i, Spain
                                          1. Oscar Fernández (med001832{at}saludalia.com)
                                          1. Instituto de Neurociencias Clínicas, Hospital Regional, Universitario Carlos Haya, Mál, Spain
                                            1. Laura Leyva (laura.leyva.exts{at}juntadeandalucia.es)
                                            1. Instituto de Neurociencias Clínicas, Hospital Regional, Universitario Carlos Haya, Mál, Spain
                                              1. Miguel Guerrero (mguerrerof{at}netscape.net)
                                              1. Servicio de Neurología, Hospital Clínico San Cecilio, Granada, Spain
                                                1. Miguel Lucas (lucas{at}us.es)
                                                1. Servicio de Biología Moleular, Hospital Universitario Virgen Macarena, Sevilla, Spain
                                                  1. Guillermo Izquierdo (lucas{at}us.es)
                                                  1. Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain
                                                    1. Fuencisla Matesanz (lindo{at}ipb.csic.es)
                                                    1. Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Inv. Cient&i, Spain
                                                      1. Ann-Christine Syvänen (ann-christine.syvanen{at}medsci.uu.se)
                                                      1. Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

                                                        Abstract

                                                        Background: IRF5 is a transcription factor involved both in the type I interferon and the toll-like receptor signalling pathways. Previously, IRF5 has been found to be associated with systemic lupus erythematosus, rheumatoid arthritis and inflammatory bowel diseases. Here we investigated whether polymorphisms in the IRF5 gene would be associated with yet another disease with features of autoimmunity, multiple sclerosis.

                                                        Materials and methods:We genotyped nine single nucleotide polymorphisms and one insertion-deletion polymorphism in the IRF5 gene in a collection of 2337 patients with MS and 2813 controls from three populations: two case-control cohorts from Spain and Sweden, and a set of MS trio families from Finland.

                                                        Results:Two SNPs (rs4728142, rs3807306) and a 5 bp insertion-deletion polymorphism located in the promoter and first intron of the IRF5 gene, showed association signals with p-values <0.001 when the data from all cohorts were combined. The predisposing alleles were present on the same common haplotype in all populations. Using electrophoretic mobility shift assays we observed allele-specific differences in protein binding for the SNP rs4728142 and the 5 bp indel, and by a proximity ligation assay we demonstrated increased binding of the transcription factor SP1 to the risk allele of the 5 bp indel.

                                                        Conclusion:These findings add IRF5 to the short list of genes shown to be associated with MS in more than one population. Our study adds to the evidence that there might be genes or pathways that are common in multiple autoimmune diseases, and that the type I interferon system is likely to be involved in the development of these diseases.

                                                        • autoimmune disease
                                                        • genetic association analysis
                                                        • interferon regulatory factor 5
                                                        • multiple sclerosis
                                                        • type I interferon system

                                                        Statistics from Altmetric.com

                                                        Request permissions

                                                        If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.