Article | Published:

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Nature Genetics volume 43, pages 761767 (2011) | Download Citation

  • A Corrigendum to this article was published on 29 August 2011

This article has been updated

Abstract

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10−8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10−6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27–positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

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Change history

  • 11 August 2011

    In the version of this article initially published, the name of author Udo Oppermann was incorrectly spelled as Udo Opperman, and the name of author Loukas Moutsianas was incorrectly spelled as Loukas Moutsianis. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We would like to thank all participating subjects with ankylosing spondylitis and healthy individuals who provided the DNA and clinical information necessary for this study. The Wellcome Trust Case Control Consortium 2 project is funded by the Wellcome Trust (083948/Z/07/Z). We also thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. The TASC study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915 and R01-AR046208. Funding was also received from the University of Texas at Houston Clinical and Translational Science Awards grant UL1RR024188, Cedars-Sinai General Clinical Research Centre grant MO1-RR00425, Intramural Research Program, NIAMS/US National Institutes of Health and Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis Research UK (Grants 19536 and 18797), by the Wellcome Trust (grant number 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme code: A91202). The Spondyloarthritis Research Consortium of Canada (SPARCC) was funded by a National Research Initiative Award from the Arthritis Society (Canada). G.P.T. was funded by a Lions Medical Research Foundation fellowship. M.A.B. is funded by a National Health and Medical Research Council (Australia) Principal Research Fellowship, and support for this study was received from a National Health and Medical Research Council (Australia) program grant (566938) and project grant (569829) and from the Australian Cancer Research Foundation and Rebecca Cooper Medical Research Foundation. P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for subject recruitment was provided by the National Institute for Health Research (NIHR), Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research Network. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02, and we thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust. We would like to thank A. Mathieu (Cagliari University) and S. Brown (Cedars-Sinai Hospital) for providing samples. The Structural Genomics Consortium is a registered charity (number 1097737) that receives funds from the Canadian Institutes for Health Research, the Canadian Foundation for Innovation, Genome Canada through the Ontario Genomics Institute, GlaxoSmithKline, Karolinska Institutet, the Knut and Alice Wallenberg Foundation, the Ontario Innovation Trust, the Ontario Ministry for Research and Innovation, Merck & Co., Inc., the Novartis Research Foundation, the Swedish Agency for Innovation Systems, the Swedish Foundation for Strategic Research and the Wellcome Trust.

Author information

Author notes

    • David M Evans
    •  & Chris C A Spencer

    These authors contributed equally to this work.

    • Matthew A Brown
    •  & Peter Donnelly

    These authors jointly directed this work.

Affiliations

  1. Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • David M Evans
    • , Alexander Dilthey
    • , Matti Pirinen
    •  & Tetyana Zayats
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Chris C A Spencer
    • , Zhan Su
    • , Gavin Band
    • , Céline Bellenguez
    • , Colin Freeman
    • , Amy Strange
    • , Gilean McVean
    •  & Peter Donnelly
  3. National Institute for Health Research Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford, UK.

    • Jennifer J Pointon
    • , David Harvey
    • , Louise Appleton
    • , Tom Wordsworth
    • , Tugce Karaderi
    • , Claire Farrar
    • , Paul Bowness
    •  & B Paul Wordsworth
  4. Structural Genomics Consortium, University of Oxford, Oxford, UK.

    • Grazyna Kochan
    •  & Udo Oppermann
  5. University of Bath, Bath, UK.

    • Millicent A Stone
  6. Department of Statistics, University of Oxford, Oxford, UK.

    • Loukas Moutsianas
  7. Department of Clinical Pharmacology, University of Oxford, Oxford, UK.

    • Stephen Leslie
  8. University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia.

    • Tony J Kenna
    • , Gethin P Thomas
    • , Linda A Bradbury
    • , Patrick Danoy
    •  & Matthew A Brown
  9. National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health (NIH), Bethesda, Maryland, USA.

    • Michael M Ward
  10. Department of Medicine/Rheumatology, Cedars-Sinai Medical Centre, Los Angeles, California, USA.

    • Michael H Weisman
  11. University of Toronto, Toronto, Ontario, Canada.

    • Robert D Inman
    •  & Dafna Gladman
  12. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

    • Walter Maksymowych
  13. Memorial University, St. John's, Newfoundland, Canada.

    • Proton Rahman
  14. National Institute for Health Research (NIHR)–Leeds Musculoskeletal Biomedical Research Unit, University of Leeds, Leeds, UK.

    • Ann Morgan
    •  & Helena Marzo-Ortega
  15. Department of Rheumatology, Norfolk & Norwich University Hospital, Norfolk, UK.

    • Karl Gaffney
  16. Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK.

    • J S Hill Gaston
  17. Repatriation General Hospital, Adelaide, Australia.

    • Malcolm Smith
  18. Serviço Especializado De Epidemiologia E Biologia Molecular, Hospital de Santo Espírito, Angra do Heroísmo, Terceira, The Azores, Portugal.

    • Jacome Bruges-Armas
    •  & Ana-Rita Couto
  19. Genetics and Arthritis Research Group, Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.

    • Jacome Bruges-Armas
  20. Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Rome, Italy.

    • Rosa Sorrentino
    •  & Fabiana Paladini
  21. Queensland Institute of Medical Research, Brisbane, Australia.

    • Manuel A Ferreira
  22. Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University Hospital, Shanghai, China.

    • Huji Xu
    • , Yu Liu
    •  & Lei Jiang
  23. Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.

    • Carlos Lopez-Larrea
    • , Roberto Díaz-Peña
    • , Antonio López-Vázquez
    •  & Hannah Blackburn
  24. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Elvira Bramon
    • , Suzannah J Bumpstead
    • , Panos Deloukas
    • , Serge Dronov
    • , Sarah Edkins
    • , Matthew Gillman
    • , Emma Gray
    • , Rhian Gwilliam
    • , Naomi Hammond
    • , Sarah E Hunt
    • , Alagurevathi Jayakumar
    • , Cordelia Langford
    • , Jennifer Liddle
    • , Owen T McCann
    • , Leena Peltonen
    • , Simon C Potter
    • , Anna Rautanen
    • , Radhi Ravindrarajah
    • , Michelle Ricketts
    • , Matthew Waller
    • , Paul Weston
    • , Pamela Whittaker
    •  & Sara Widaa
  25. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Australia.

    • Jenefer M Blackwell
  26. Genetics and Infection Laboratory, Cambridge Institute of Medical Research, Addenbrooke's Hospital, Cambridge, UK.

    • Jenefer M Blackwell
  27. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Juan P Casas
  28. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Aiden Corvin
  29. Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, Wales.

    • Nicholas Craddock
  30. Molecular and Physiological Sciences, The Wellcome Trust, London, UK.

    • Audrey Duncanson
  31. Centre for Gastroenterology, Bart's and the London School of Medicine and Dentistry, London, UK.

    • Janusz Jankowski
  32. Clinical Neurosciences, St. George's University of London, London, UK.

    • Hugh S Markus
  33. Division of Genetics and Molecular Medicine, King's College London, London, UK.

    • Christopher G Mathew
    •  & Richard C Trembath
  34. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  35. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  36. Social, Genetic and Developmental Psychiatry Centre, King's College London Institute of Psychiatry, Denmark Hill, London, UK.

    • Robert Plomin
  37. Department of Cardiovascular Science, University of Leicester, Glenfield General Hospital, Leicester, UK.

    • Nilesh Samani
  38. University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, UK.

    • Stephen J Sawcer
  39. Glaucoma Research Unit, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

    • Ananth C Viswanathan
  40. Department of Genetics, University College London Institute of Ophthalmology, London, UK.

    • Ananth C Viswanathan
  41. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK.

    • Nicholas W Wood
  42. Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • John D Reveille

Consortia

  1. The Australo-Anglo-American Spondyloarthritis Consortium (TASC)

    A full list of members is provided in the Supplementary Note.

  2. the Wellcome Trust Case Control Consortium 2 (WTCCC2)

    A full list of members is provided in the Supplementary Note.

  3. Spondyloarthritis Research Consortium of Canada (SPARCC)

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Contributions

M.A.B., L.A.B., C. Farrar, J.D.R., J.J.P., B.P.W., D.G., W.M. and P.R. oversaw cohort collection for the discovery and replication datasets. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.J.B., S.D., S.E., E.G., C.L. and L.P.) executed GWAS sample handling, genotyping and quality control. The WTCCC2 data and analysis group (A.S., C.C.A.S., G.B., C.B., C. Freeman and P. Donnelly), D.M.E. and M.A.B. performed statistical analyses. M.A.B., D.M.E., C.C.A.S. and P. Donnelly contributed to writing the manuscript. The WTCCC2 management committee (J.M.B., E.B., M.A.B., J.P.C., A.C., P. Deloukas, P. Donnelly (chairperson), A. Duncanson, J.J., J.L., H.S.M., C.G.M., C.N.A.P., L.P., R.P., A.R., S.J.S., R.C.T., A.C.V. and N.W.W.) monitored the execution of the GWAS. D.H., G.K. and U.O. performed analyses of recombinant ERAP1 function. T.J.K. and G.P.T. performed gene expression, cell count and ERAP1 sheddase functional studies. Other authors contributed variously to sample collection and all other aspects of the study. All authors reviewed the final manuscript.

Competing interests

The University of Queensland has applied for patents relating to material presented in this manuscript in Australia, Europe and the United States.

Corresponding authors

Correspondence to Matthew A Brown or Peter Donnelly.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1–6.

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DOI

https://doi.org/10.1038/ng.873

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