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.

  • Letter
  • Published:

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis

Abstract

Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS)1, it has been difficult to demonstrate which variants are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance2. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS)3,4, but not with other autoimmune conditions such as rheumatoid arthritis5, psoriasis6 and Crohn’s disease7. By analysing MS GWAS3,4 data in conjunction with the 1000 Genomes Project data8 we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS9,10,11, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: MS-associated TNFRSF1A region and rs1800693-dependent splicing.
Figure 2: Δ6-TNFR1 localization and analysis of isoform association.
Figure 3: Δ6-TNFR1 solubility and TNF binding and neutralization.

Similar content being viewed by others

References

  1. Lander, E. S. Initial impact of the sequencing of the human genome. Nature 470, 187–197 (2011)

    Article  ADS  CAS  Google Scholar 

  2. Goldstein, D. B. Common genetic variation and human traits. N. Engl. J. Med. 360, 1696–1698 (2009)

    Article  CAS  Google Scholar 

  3. De Jager, P. L. et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genet. 41, 776–782 (2009)

    Article  CAS  Google Scholar 

  4. Sawcer, S. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011)

    Article  ADS  CAS  Google Scholar 

  5. Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature Genet. 42, 508–514 (2010)

    Article  CAS  Google Scholar 

  6. Strange, A. et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nature Genet. 42, 985–990 (2010)

    Article  CAS  Google Scholar 

  7. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed ’Crohn’s disease susceptibility loci. Nature Genet. 42, 1118–1125 (2010)

    Article  CAS  Google Scholar 

  8. The 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)

  9. Bosch, X., Saiz, A. & Ramos-Casals, M. Monoclonal antibody therapy-associated neurological disorders. Nature Rev. Neurol. 7, 165–172 (2011)

    Article  CAS  Google Scholar 

  10. van Oosten, B. W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47, 1531–1534 (1996)

    Article  CAS  Google Scholar 

  11. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 53, 457–465 (1999)

  12. Howie, B. N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009)

    Article  Google Scholar 

  13. Chen, M. & Manley, J. L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nature Rev. Mol. Cell Biol. 10, 741–754 (2009)

    Article  CAS  Google Scholar 

  14. Schütze, S., Tchikov, V. & Schneider-Brachert, W. Regulation of TNFR1 and CD95 signalling by receptor compartmentalization. Nature Rev. Mol. Cell Biol. 9, 655–662 (2008)

    Article  Google Scholar 

  15. Kimberley, F. C., Lobito, A. A., Siegel, R. M. & Screaton, G. R. Falling into TRAPS – receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. Arthritis Res. Ther. 9, 217 (2007)

    Article  Google Scholar 

  16. Hofman, F. M., Hinton, D. R., Johnson, K. & Merrill, J. E. Tumor necrosis factor identified in multiple sclerosis brain. J. Exp. Med. 170, 607–612 (1989)

    Article  CAS  Google Scholar 

  17. Sharief, M. K. & Hentges, R. Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis. N. Engl. J. Med. 325, 467–472 (1991)

    Article  CAS  Google Scholar 

  18. Probert, L. et al. TNFR1 signalling is critical for the development of demyelination and the limitation of T-cell responses during immune-mediated CNS disease. Brain 123, 2005–2019 (2000)

    Article  Google Scholar 

  19. Baker, D. et al. Control of established experimental allergic encephalomyelitis by inhibition of tumor necrosis factor (TNF) activity within the central nervous system using monoclonal antibodies and TNF receptor-immunoglobulin fusion proteins. Eur. J. Immunol. 24, 2040–2048 (1994)

    Article  CAS  Google Scholar 

  20. Liu, J. et al. TNF is a potent anti-inflammatory cytokine in autoimmune-mediated demyelination. Nature Med. 4, 78–83 (1998)

    Article  CAS  Google Scholar 

  21. Taoufik, E. et al. Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-κB. Brain 134, 2722–2735 (2011)

    Article  Google Scholar 

  22. Brambilla, R. et al. Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain 134, 2736–2754 (2011)

    Article  Google Scholar 

  23. Feldmann, M. & Steinman, L. Design of effective immunotherapy for human autoimmunity. Nature 435, 612–619 (2005)

    Article  ADS  CAS  Google Scholar 

  24. Evans, D. M. et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature Genet. 43, 761–767 (2011)

    Article  CAS  Google Scholar 

  25. Mells, G. F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nature Genet. 43, 329–332 (2011)

    Article  CAS  Google Scholar 

  26. Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 1502–1517 (2008)

    Article  CAS  Google Scholar 

  27. Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881–888 (2008)

    Article  ADS  CAS  Google Scholar 

  28. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nature Genet. 39, 906–913 (2007)

    Article  CAS  Google Scholar 

  29. Chan, F. K. et al. Fluorescence resonance energy transfer analysis of cell surface receptor interactions and signaling using spectral variants of the green fluorescent protein. Cytometry 44, 361–368 (2001)

    Article  CAS  Google Scholar 

  30. James, J. R., Oliveira, M. I., Carmo, A. M., Iaboni, A. & Davis, S. J. A rigorous experimental framework for detecting protein oligomerization using bioluminescence resonance energy transfer. Nature Methods 3, 1001–1006 (2006)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the volunteers who donated blood samples, the IMSGC and WTCCC2 for data access, A. Auton for help with association analysis data preparation, G. R. Screaton for providing TNFR1 constructs, and A. Vincent and N. Willcox for critical reading of the manuscript. Work in the authors’ laboratories is supported by the UK Medical Research Council (MRC), the European Union through grant FP7/2007-2013 (SYBILLA), the Naomi Bramson Trust (L.F.), and the Wellcome Trust (090532/Z/09/Z and 086084/Z/08/Z; G.M.). A.P.G., A.H., L.L., O.A.L. and D.P. are supported by an MRC studentship, the Deutsche Forschungsgemeinschaft, a Christopher Welch Scholarship, funding from the MRC and the MS Society, and a Dorothy Hodgkin Postgraduate Award, respectively.

Author information

Authors and Affiliations

Authors

Contributions

A.P.G. contributed to the study design, all experiments, and drafting and writing of the manuscript. C.A.D. contributed to the study design, volunteer recruitment, coordination of blood sample collection, blood and serum sample experiments, and drafting and writing of the manuscript. K.E.A. contributed to the study design, coordination of blood sample collection, recombinant protein production and purification, and manuscript drafting. A.H. and O.A.L. performed blood sample obtainment. D.K.X. and G.M. performed the statistical association analyses and G.M. contributed to drafting and writing of the manuscript. F.B., G.P. and M.M. performed the mass spectrometric analyses. G.K. contributed to lentiviral transduction experiment design. L.L. contributed to volunteer recruitment and genotype double-scoring. S.P. contributed to the confocal microscopy, protein purification and surface plasmon resonance experiments. D.P. performed initial minigene experiments. J.H.F. and S.J.D. helped with BRET experiments. A.H. and R.G. provided patient serum samples. F.C.N. helped with minigene experimental design and polysome profiling assays. R.M.S. provided TNFR1 constructs and contributed to study conception. J.I.B. helped with conception of the study and writing the final manuscript. L.F. contributed to conception, design and coordination of the study, data analysis, and drafting and writing of the manuscript.

Corresponding author

Correspondence to Lars Fugger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-15. (PDF 1829 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gregory, A., Dendrou, C., Attfield, K. et al. TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488, 508–511 (2012). https://doi.org/10.1038/nature11307

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11307

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research