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

Nature volume 488, pages 508–511 (2012)Cite this article

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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.

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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.

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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.

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Author notes

  1. Adam P. Gregory and Calliope A. Dendrou: These authors contributed equally to this work.

Authors and Affiliations

  1. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK,

    Adam P. Gregory, Gurman Kaur, Divya Punwani, James H. Felce, Simon J. Davis & Lars Fugger

  2. Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK,

    Calliope A. Dendrou, Kathrine E. Attfield, Aiden Haghikia, Lydia Lambert, Oliver A. Leach, Simone Prömel & Lars Fugger

  3. Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum, 44791 Bochum, Germany,

    Aiden Haghikia & Ralf Gold

  4. Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK,

    Dionysia K. Xifara & Gil McVean

  5. Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany,

    Falk Butter & Matthias Mann

  6. Molecular Proteomics Laboratory, Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine Universität Düsseldorf, D-40225 Düsseldorf, Germany,

    Gereon Poschmann

  7. Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark,

    Finn C. Nielsen

  8. Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH, 10 Center Drive, Bethesda, 20892-1930, Maryland, USA

    Richard M. Siegel

  9. Richard Doll Building, Roosevelt Drive, University of Oxford, Oxford OX3 7DG, UK,

    John I. Bell

  10. Clinical Institute, Aarhus University Hospital, Skejby Sygehus, 8200 N Aarhus, Denmark,

    Lars Fugger

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  1. Adam P. Gregory
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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.

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The authors declare no competing financial interests.

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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

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