Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection

Genes & Immunity volume 12, pages 40–45 (2011)Cite this article

Subjects

Abstract

In recent reports, IRF5 polymorphisms showed significant association with multiple sclerosis (MS) susceptibility in three studied populations and Irf5-deficient mice exhibited an increased susceptibility to viral infection, linked to a significant decrease in the induction of serum type I interferon (IFN). In the present study, we evaluated the association of two IRF5 polymorphisms with MS predisposition and we also addressed whether these polymorphisms were associated with active replication of human herpes virus-6 (HHV-6) observed in a subgroup of MS patients, and/or with response to IFN-β therapy. A total of 1494 MS patients and 1506 ethnically matched controls were genotyped for rs4728142 and rs3807306 with TaqMan pre-designed assays. One hundred and six patients were classified as responders to IFN-β therapy (no relapses/increases in EDSS over the 2-year follow-up) and 112 as non-responders (at least two relapses or an increase in expanded disability status scale (EDSS) of at least one point during the same period). The combined analysis of available datasets yielded an effect size on MS with odds ratio (OR)Mantel−Haenszel=1.14 (P<0.002) for the IRF5 polymorphisms rs4728142 and rs3807306. Additionally, trends for association were observed between rs3807306T and infection with HHV-6 [p=0.05, OR (95% CI)=1.56 (1.00–2.44)] and response to IFN-β therapy [P=0.09, OR (95% CI)=1.39 (0.95–2.05)].

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Tamura T, Yanai H, Savitsky D, Taniguchi T . The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol 2008; 26: 535–584.

    Article  CAS  PubMed  Google Scholar 

  2. Hiscott J . Triggering the innate antiviral response through IRF-3 activation. J Biol Chem 2007; 282: 15325–15329.

    Article  CAS  PubMed  Google Scholar 

  3. Barnes BJ, Moore PA, Pitha PM . Virus-specific activation of a novel interferon regulatory factor, IRF-5, results in the induction of distinct interferon alpha genes. J Biol Chem 2001; 276: 23382–23390.

    Article  CAS  PubMed  Google Scholar 

  4. Barnes BJ, Richards J, Mancl M, Hanash S, Beretta L, Pitha PM . Global and distinct targets of IRF-5 and IRF-7 during innate response to viral infection. J Biol Chem 2004; 279: 45194–45207.

    Article  CAS  PubMed  Google Scholar 

  5. Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM . Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death. Cancer Res 2003; 63: 6424–6431.

    CAS  PubMed  Google Scholar 

  6. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 2005; 434: 243–249.

    Article  CAS  PubMed  Google Scholar 

  7. Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005; 76: 528–537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rueda B, Reddy MV, Gonzalez-Gay MA, Balsa A, Pascual-Salcedo D, Petersson IF et al. Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis. Arthritis Rheum 2006; 54: 3815–3819.

    Article  CAS  PubMed  Google Scholar 

  9. Dideberg V, Kristjansdottir G, Milani L, Libioulle C, Sigurdsson S, Louis E et al. An insertion-deletion polymorphism in the interferon regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases. Hum Mol Genet 2007; 16: 3008–3016.

    Article  CAS  PubMed  Google Scholar 

  10. Miceli-Richard C, Comets E, Loiseau P, Puechal X, Hachulla E, Mariette X . Association of an IRF5 gene functional polymorphism with Sjogren's syndrome. Arthritis Rheum 2007; 56: 3989–3994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shimane K, Kochi Y, Yamada R, Okada Y, Suzuki A, Miyatake A et al. A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. Ann Rheum Dis 2009; 68: 377–383.

    Article  CAS  PubMed  Google Scholar 

  12. Kristjansdottir G, Sandling JK, Bonetti A, Roos IM, Milani L, Wang C et al. Interferon regulatory factor 5 (IRF5) gene variants are associated with multiple sclerosis in three distinct populations. J Med Genet 2008; 45: 362–369.

    Article  CAS  PubMed  Google Scholar 

  13. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851–862.

    Article  CAS  PubMed  Google Scholar 

  14. Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. Nat Genet 2009; 41: 824–828.

    Article  Google Scholar 

  15. Fotheringham J, Jacobson S . Human herpesvirus 6 and multiple sclerosis: potential mechanisms for virus-induced disease. Herpes 2005; 12: 4–9.

    PubMed  Google Scholar 

  16. Vosslamber S, van Baarsen LG, Verweij CL . Pharmacogenomics of IFN-beta in multiple sclerosis: towards a personalized medicine approach. Pharmacogenomics 2009; 10: 97–108.

    Article  CAS  PubMed  Google Scholar 

  17. Yanai H, Chen HM, Inuzuka T, Kondo S, Mak TW, Takaoka A et al. Role of IFN regulatory factor 5 transcription factor in antiviral immunity and tumor suppression. Proc Natl Acad Sci USA 2007; 104: 3402–3407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Paun A, Reinert JT, Jiang Z, Medin C, Balkhi MY, Fitzgerald KA et al. Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response. J Biol Chem 2008; 283: 14295–14308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Baccala R, Hoebe K, Kono DH, Beutler B, Theofilopoulos AN . TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat Med 2007; 13: 543–551.

    Article  CAS  PubMed  Google Scholar 

  20. O’Neill LA . Targeting signal transduction as a strategy to treat inflammatory diseases. Nat Rev Drug Discov 2006; 5: 549–563.

    Article  PubMed  Google Scholar 

  21. Knox KK, Brewer JH, Henry JM, Harrington DJ, Carrigan DR . Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease. Clin Infect Dis 2000; 31: 894–903.

    Article  CAS  PubMed  Google Scholar 

  22. Coyle PK, Hartung HP . Use of interferon beta in multiple sclerosis: rationale for early treatment and evidence for dose- and frequency-dependent effects on clinical response. Mult Scler 2002; 8: 2–9.

    Article  CAS  PubMed  Google Scholar 

  23. O’Doherty C, Villoslada P, Vandenbroeck K . Pharmacogenomics of Type I interferon therapy: a survey of response-modifying genes. Cytokine Growth Factor Rev 2007; 18: 211–222.

    Article  PubMed  Google Scholar 

  24. Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F et al. Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. Hum Mol Genet 2009; 18: 767–778.

    Article  CAS  PubMed  Google Scholar 

  25. Wies E, Hahn AS, Schmidt K, Viebahn C, Rohland N, Lux A et al. The Kaposi's Sarcoma-associated Herpesvirus-encoded vIRF-3 Inhibits Cellular IRF-5. J Biol Chem 2009; 284: 8525–8538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barro M, Patton JT . Rotavirus NSP1 inhibits expression of type I interferon by antagonizing the function of interferon regulatory factors IRF3, IRF5, and IRF7. J Virol 2007; 81: 4473–4481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rullo OJ, Woo JM, Wu H, Hoftman AD, Maranian P, Brahn BA et al. Association of IRF5 polymorphisms with activation of the interferon alpha pathway. Ann Rheum Dis 2010; 69: 611–617.

    Article  CAS  PubMed  Google Scholar 

  28. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.

    Article  CAS  PubMed  Google Scholar 

  29. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

    Article  CAS  PubMed  Google Scholar 

  30. Hymas W, Stevenson J, Taggart EW, Hillyard D . Use of lyophilized standards for the calibration of a newly developed real time PCR assay for human herpes type six (HHV6) variants A and B. J Virol Methods 2005; 128: 143–150.

    Article  CAS  PubMed  Google Scholar 

  31. Nitsche A, Muller CW, Radonic A, Landt O, Ellerbrok H, Pauli G et al. Human herpesvirus 6A DNA is detected frequently in plasma but rarely in peripheral blood leukocytes of patients after bone marrow transplantation. J Infect Dis 2001; 183: 130–133.

    Article  CAS  PubMed  Google Scholar 

  32. Alvarez-Lafuente R, De las Heras V, Bartolome M, Picazo JJ, Arroyo R . Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection. Arch Neurol 2004; 61: 1523–1527.

    Article  PubMed  Google Scholar 

  33. Okuda DT, Srinivasan R, Oksenberg JR, Goodin DS, Baranzini SE, Beheshtian A et al. Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures. Brain 2009; 132: 250–259.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants to KV from the European Community's Seventh Framework Program [FP7/2007-2013] under grant agreement no. 212877 (UEPHA*MS; www.reem.es/uepha-ms/), by grants from the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (Feder) (FIS-PI070353 to EU and FIS-PI070369 to MF-A), Red Española de Esclerosis Múltiple (RETICS-REEM RD07/0060; www.reem.es) and ‘Fundación Alfonso Martín Escudero’. R A-L is recipient of a research contract of the Spanish Health Ministry (CP07/00273).

Author information

Authors and Affiliations

  1. Neurogenomiks, University of the Basque Country (UPV/EHU), Leioa, Spain

    K Vandenbroeck, I Alloza & B Swaminathan

  2. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

    K Vandenbroeck

  3. Servicio de Neurología, Hospital de Basurto, Bilbao, Spain

    A Antigüedad

  4. Área de Neurociencias, Inst. Investigación Sanitaria Biodonostia, San Sebastián, Spain

    D Otaegui & J Olascoaga

  5. Servicio de Genética, Hospital de Basurto, Bilbao, Spain

    M G Barcina

  6. Multiple Sclerosis Unit, Neurology Dept. Hospital Clínico S. Carlos, Madrid, Spain

    V de las Heras, M Bartolomé, R Arroyo & R Alvarez-Lafuente

  7. Immunology Dept. Hospital Clínico S. Carlos, Madrid, Spain

    M Fernández-Arquero, M C Cénit & E Urcelay

Authors
  1. K Vandenbroeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I Alloza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Swaminathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Antigüedad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Otaegui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Olascoaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M G Barcina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V de las Heras
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Bartolomé
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Fernández-Arquero
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R Arroyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. R Alvarez-Lafuente
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. M C Cénit
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. E Urcelay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Urcelay.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vandenbroeck, K., Alloza, I., Swaminathan, B. et al. Validation of IRF5 as multiple sclerosis risk gene: putative role in interferon beta therapy and human herpes virus-6 infection. Genes Immun 12, 40–45 (2011). https://doi.org/10.1038/gene.2010.46

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2010.46

Keywords

This article is cited by

Search

Advanced search

Quick links