J Med Genet 45:362-369 doi:10.1136/jmg.2007.055012
  • Original article

Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations

Open Access
  1. G Kristjansdottir1,
  2. J K Sandling1,
  3. A Bonetti2,
  4. I M Roos3,
  5. L Milani1,
  6. C Wang1,
  7. S M Gustafsdottir4,
  8. S Sigurdsson1,
  9. A Lundmark1,
  10. P J Tienari2,
  11. K Koivisto5,
  12. I Elovaara6,
  13. T Pirttilä7,
  14. M Reunanen8,
  15. L Peltonen9,
  16. J Saarela9,
  17. J Hillert3,
  18. T Olsson10,
  19. U Landegren4,
  20. A Alcina11,
  21. O Fernández12,
  22. L Leyva12,
  23. M Guerrero13,
  24. M Lucas14,
  25. G Izquierdo15,
  26. F Matesanz11,
  27. A-C Syvänen1
  1. 1
    Molecular Medicine, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  2. 2
    Department of Neurology, Helsinki University Central Hospital and Molecular Neurology Research Program, University of Helsinki, Helsinki, Finland
  3. 3
    Department of Clinical Neuroscience, Division of Neurology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
  4. 4
    Rudbeck Laboratory, Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
  5. 5
    Central Hospital of Seinäjoki, Seinäjoki, Finland
  6. 6
    Department of Neurology, University of Tampere and Tampere University Hospital, Tampere, Finland
  7. 7
    Department of Neurology and Neuroscience, University of Kuopio and Kuopio University Hospital, Kuopio, Finland
  8. 8
    Department Neurology, University of Oulu and Oulu University Hospital, Oulu, Finland
  9. 9
    Department of Molecular Medicine, Biomedicum, National Public Health Institute, Helsinki, Finland
  10. 10
    Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Stockholm, Sweden
  11. 11
    Instituto de Parasitología y Biomedicina López Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain
  12. 12
    Servicio de Neurología, Instituto de Neurociencias Clínicas, Hospital Regional, Universitario Carlos Haya, Málaga, Spain
  13. 13
    Servicio de Neurología, Hospital Clínico San Cecilio, Granada, Spain
  14. 14
    Servicio de Biología Moleular, Hospital Universitario Virgen Macarena, Sevilla, Spain
  15. 15
    Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain
  1. Professor A-C Syvänen, Molecular Medicine, Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden; ann-christine.syvanen{at}
  • Received 27 September 2007
  • Revised 29 January 2008
  • Accepted 31 January 2008
  • Published Online First 19 February 2008


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 (MS).

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 single nucleotide polymorphism (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 values of p<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.


  • Competing interests: None.

  • Funding: Financial support for the study was provided by the Swedish Research Council and the Knut and Alice Wallenberg Foundation (to A-CS), the Academy of Finland, the Sigrid Juselius Foundation and Helsinki University Central Hospital (to PJT and LP), the Center of Excellence for Disease Genetics of the Academy of Finland (to LP), the Paulo Foundation (to PJT), the Finnish Cultural Foundation (to PJT and AB), the Helsinki Biomedical Graduate School (to AB), the Nils and Bibbi Jensen’s Foundation (to JH) and by the grants PN-SAF 2006–02023 (to AA) and FIS-PI041298 (to FM).

  • Ethics approval: The study was approved by the respective local ethics committees in Spain, Sweden and Finland.

  • Patient consent: Informed consent was obtained from the patients for publication of their details in this report.

  • ▸ Additional tables are published online only at

    GK and JKS contributed equally to this work