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:

Single-nucleotide polymorphisms in HLA- and non-HLA genes associated with the development of antibodies to interferon-β therapy in multiple sclerosis patients

The Pharmacogenomics Journal volume 12, pages 238–245 (2012)Cite this article

Abstract

Interferons-β (IFN-β) are the most widely used immunomodulatory drugs for treatment of multiple sclerosis (MS). The development of neutralizing antibodies (NABs) against IFN-β is one of the main reasons for treatment failure. While formulation of the drug has a proven impact on the development of NABs, the genetic predisposition to develop antibodies is poorly understood. We performed genome-wide single-nucleotide polymorphism (SNP) genotyping in 362 MS patients of whom 178 had developed and 184 had not developed antibodies on IFN-β therapy. Four candidate SNPs were validated in an independent cohort of 350 antibody-positive and 468 antibody-negative MS patients. One SNP within the human leucocyte antigen (HLA) region (rs9272105, P-value: 3.56 × 10−10) and one SNP in an intergenic region on chromosome 8q24.3 (rs4961252, P-value: 2.92 × 10−8) showed a genome-wide significant association with the anti-IFN-β antibody titers. We found no interaction between the genome-wide significant SNPs (rs9272105 and rs4961252) in our study and the previously described HLA-DR*0401 or *0408 alleles, indicating an additive effect of SNPs and HLA alleles. Testing for these SNPs and the HLA-DR*0401 or *0408 alleles allows to identify patients at risk to develop antibodies to IFN-β and may provide helpful information for individual treatment decisions.

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG . Multiple sclerosis. N Engl J Med 2000; 343: 938–952.

    Article  CAS  PubMed  Google Scholar 

  2. Compston A, Coles A . Multiple sclerosis. Lancet 2002; 359: 1221–1231.

    Article  PubMed  Google Scholar 

  3. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989; 112 (Part 1): 133–146.

    Article  PubMed  Google Scholar 

  4. Sospedra M, Martin R . Immunology of multiple sclerosis. Annu Rev Immunol 2005; 23: 683–747.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. de Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 2009; 41: 776–782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Oksenberg JR, Baranzini SE, Sawcer S, Hauser SL . The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 2008; 9: 516–526.

    Article  CAS  PubMed  Google Scholar 

  8. Ann MR, Rudick RA . Drug insight: interferon treatment in multiple sclerosis. Nat Clin Pract Neurol 2006; 2: 34–44.

    Article  Google Scholar 

  9. Bertolotto A, Deisenhammer F, Gallo P, Solberg SP . Immunogenicity of interferon beta: differences among products. J Neurol 2004; 251 (Suppl 2): II15–II24: II15–II24.

    PubMed  Google Scholar 

  10. Hemmer B, Stuve O, Kieseier B, Schellekens H, Hartung HP . Immune response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis. Lancet Neurol 2005; 4: 403–412.

    Article  CAS  PubMed  Google Scholar 

  11. Farrell RA, Giovannoni G . Measuring and management of anti-interferon beta antibodies in subjects with multiple sclerosis. Mult Scler 2007; 13: 567–577.

    Article  CAS  PubMed  Google Scholar 

  12. Hesse D, Sellebjerg F, Sorensen PS . Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity. Neurology 2009; 73: 372–377.

    Article  CAS  PubMed  Google Scholar 

  13. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. Neurology 1996; 47: 889–894.

    Article  Google Scholar 

  14. Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K et al. Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 2003; 362: 1184–1191.

    Article  CAS  PubMed  Google Scholar 

  15. Kappos L, Clanet M, Sandberg-Wollheim M, Radue EW, Hartung HP, Hohlfeld R et al. Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year controlled study. Neurology 2005; 65: 40–47.

    Article  CAS  PubMed  Google Scholar 

  16. Francis GS, Rice GP, Alsop JC . Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology 2005; 65: 48–55.

    Article  CAS  PubMed  Google Scholar 

  17. Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J et al. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS task force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 2005; 12: 817–827.

    Article  CAS  PubMed  Google Scholar 

  18. Goodin DS, Frohman EM, Hurwitz B, O'Connor PW, Oger JJ, Reder AT et al. Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007; 68: 977–984.

    Article  CAS  PubMed  Google Scholar 

  19. Polman CH, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung HP, Hemmer B et al. Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 2010; 9: 740–750.

    Article  CAS  PubMed  Google Scholar 

  20. Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermuller J, Stadler PF et al. HLA-DRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis. Am J Hum Genet 2008; 83: 219–227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pachner AR . An improved ELISA for screening for neutralizing anti-IFN-beta antibodies in MS patients. Neurology 2003; 61: 1444–1446.

    Article  CAS  PubMed  Google Scholar 

  22. Pachner A, Narayan K, Price N, Hurd M, Dail D . MxA gene expression analysis as an interferon-beta bioactivity measurement in patients with multiple sclerosis and the identification of antibody-mediated decreased bioactivity. Mol Diagn 2003; 7: 17–25.

    PubMed  Google Scholar 

  23. Deisenhammer F . Neutralizing antibodies to interferon-beta and other immunological treatments for multiple sclerosis: prevalence and impact on outcomes. CNS Drugs 2009; 23: 379–396.

    Article  CAS  PubMed  Google Scholar 

  24. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O'Connor P et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE Trial. Neurology 2002; 59: 1496–1506.

    Article  CAS  PubMed  Google Scholar 

  25. Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002; 359: 1453–1460.

    Article  CAS  PubMed  Google Scholar 

  26. van der Voort LF, Gilli F, Bertolotto A, Knol DL, Uitdehaag BM, Polman CH et al. Clinical effect of neutralizing antibodies to interferon beta that persist long after cessation of therapy for multiple sclerosis. Arch Neurol 2010; 67: 402–407.

    Article  PubMed  Google Scholar 

  27. Tilghman RW, Parsons JT . Focal adhesion kinase as a regulator of cell tension in the progression of cancer. Semin Cancer Biol 2008; 18: 45–52.

    Article  CAS  PubMed  Google Scholar 

  28. Stranger BE, Forrest MS, Clark AG, Minichiello MJ, Deutsch S, Lyle R et al. Genome-wide associations of gene expression variation in humans. PLoS Genet 2005; 1: e78.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Johnson AD, Handsaker RE, Pulit S, Nizzari MM, O'Donnell CJ, de Bakker PIW . SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 2008; 24: 2938–2939.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge expert technical assistance by V Grummel, S Damast, M Ködel and S Sauer. We have filed a patent for diagnostic testing of SNPs rs9272105, rs34369284 and rs4961252. This study was supported by the German Ministry for Education and Research (BMBF, ‘German Competence Network Multiple Sclerosis’ (KKNMS), Control-MS, 01GI0917) and the DFG He2386/7-1.

Author information

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Munich, Germany

    F Weber, C Wolf, M Uhr, Th Bettecken, F Holsboer & B Müller-Myhsok

  2. Department of Neurology, Klinikum rechts der Isar, Technische Universität, Munich, Germany

    S Cepok, A Berthele, D Buck & B Hemmer

  3. Department of Neurology, University Hospital, University of Düsseldorf, Düsseldorf, Germany

    H P Hartung

Authors
  1. F Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Cepok
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Berthele
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Uhr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Th Bettecken
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Buck
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H P Hartung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F Holsboer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. B Müller-Myhsok
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Hemmer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Hemmer.

Ethics declarations

Competing interests

The financial disclosure is as follows: Dr Buck has received personal compensation as a speaker from Biogen Idec and Merck Serono and research support from Merck Serono. Dr Cepok has received personal compensation as a speaker from Bayer Vital and research support from Bayer Vital. Dr Berthele received lecture fees and consulting honoraries from Biogen Idec, Bayer Healthcare, Novartis, Merck Serono and Teva and grant support from Bayer Healthcare. Dr Hartung received honoraria for consulting and speaking and travel support from Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis and Teva/Sanofi-Aventis with approval by the Rector of Heinrich-Heine-Universität Düsseldorf. The Department of Neurology, Heinrich-Heine-Universität Düsseldorf, with approval of the Rector of Heinrich-Heine-Universität Düsseldorf, received unrestricted research grants from Bayer Schering, Biogen Idec, Novartis and Teva to determine NAb levels in sera from treated patients with MS. Dr Hemmer has received in the past 3 years board membership and/or consulting fees from Novartis, Bayer Schering, Biogen Idec, Merck Serono, Roche, Micromet and Novartis. He has also received grant support from Novartis, Bayer Schering, Biogen Idec, Merck Serono and Teva. F. Weber received honoraria for speaking from Bayer-Schering AG, Biogen-Idec and Orion Pharma, for consultancy from Pfizer-Pharma and Orion Pharma, grant support from Bayer-Schering AG, TEVA and Merck-Serono.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weber, F., Cepok, S., Wolf, C. et al. Single-nucleotide polymorphisms in HLA- and non-HLA genes associated with the development of antibodies to interferon-β therapy in multiple sclerosis patients. Pharmacogenomics J 12, 238–245 (2012). https://doi.org/10.1038/tpj.2011.14

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2011.14

Keywords

This article is cited by

Search

Advanced search

Quick links