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Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Nature Genetics volume 45, pages 730–738 (2013)Cite this article

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Abstract

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

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Figure 1: IL6R polymorphism alters IL-6R serum concentrations.
Figure 2: Ankylosing spondylitis susceptibility associations in the MHC region conditioning on the HLA-B*27–tagging SNP rs116488202 and further conditioning on the HLA-A*02–tagging SNP rs2394250.
Figure 3: Ankylosing spondylitis genetic susceptibility loci overlap with those of other autoimmune diseases.

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Acknowledgements

We 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 acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls, funded by the Wellcome Trust. We thank J.C. Barrett for contributing the design of the Immunochip and for helpful analytical discussion, as well as E. Gray, S. Bumpstead, D. Simpkin and the staff of the Wellcome Trust Sanger Institute Sample Management and Genotyping teams for their genotyping and analytical contributions. The Australo-Anglo-American Spondyloarthritis Consortium (TASC) study was funded by National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) grants P01-052915 and R01-AR046208. Funding was also received from University of Texas at Houston Clinical and Translational Science Award (CTSA) UL1RR024188, Cedars-Sinai General Clinical Research Center (GCRC) grant MO1-RR00425, the Intramural Research Program, NIAMS, US National Institutes of Health and the Rebecca Cooper Foundation (Australia). This study was funded, in part, by Arthritis Research UK (grants 19536 and 18797), by the Wellcome Trust (grant 076113) and by the Oxford Comprehensive Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme A91202). We thank A. Harrison (University of Otago) for his contribution to the New Zealand ankylosing spondylitis cohort. H.X. was funded by National Natural Science Foundation of China grants 81020108029 and 30872339. Portuguese sample collection was performed by COnhecer a Realidade PORtuguesa sobre a Espondilite Anquilosante (CORPOREA Study Group), coordinated by F.M.P.-S. and supported by Bolsa Investigação da Sociedade Portuguesa de Reumatologia/Schering-Plough 2007. The Spanish ankylosing spondylitis case collection was supported by Spanish grant FICYT PC-10-70-Fondos FEDER European Union. The Spondyloarthritis Research Consortium of Canada (SPARCC) was funded by a National Research Initiative Award from the Arthritis Society (Canada). French sample collection was performed by the Groupe Française d'Etude Génétique des Spondylarthrites, coordinated by R. Said-Nahal and funded by Agence Nationale de Recherche GEnetics, Microbiota, Inflammation and Spondyloarthritis (GEMISA) grant ANR-10-MIDI-0002. We thank the Norwegian Bone Marrow Donor registry for providing data from healthy Norwegian controls. W.P.M. is a Medical Scientist of Alberta Innovates–Health Solutions. The Psoriatic Arthritis Program is supported by the Krembil Foundation and the Arthritis Society. P.C.R. is funded by the National Health and Medical Research Council (Australia) (NHMRC) and Arthritis Australia. J.Y. is supported by NHMRC grants 613672 and 1011506. M. Ward is supported by the Intramural Research Program, NIAMS, US National Institutes of Health. D.E. is supported by the research council of Ghent University and by the Fund for Scientific Research Flanders. M.A.B. is funded by a National Health and Medical Research Council (Australia) Senior 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 the Rebecca Cooper Medical Research Foundation. We thank A. Gardiner and the Brisbane Convention and Exhibition Centre for their assistance in preparing the manuscript. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and the Spondyloarthritis Association of America in case recruitment. Additional financial and technical support for subject recruitment was provided by the NIHR Oxford Musculoskeletal Biomedical Research Unit and NIHR Thames Valley Comprehensive Local Research and by an unrestricted educational grant from Abbott Laboratories.

Author information

Authors and Affiliations

  1. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia

    Adrian Cortes, Johanna Hadler, Philip C Robinson, Paul Leo, Katie Cremin, Karena Pryce, Jessica Harris, Linda A Bradbury, Tony J Kenna, Jian Yang & Matthew A Brown

  2. National Institute for Health Research (NIHR) Oxford Musculoskeletal Biomedical Research Unit, Nuffield Orthopaedic Centre, Headington, Oxford, UK

    Jenny P Pointon, Tugce Karaderi, Louise Appleton, Claire Farrah, Jonathan Lau, Paul Bowness & Bryan Paul Wordsworth

  3. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea

    Seunghun Lee, Kyung Bin Joo & Tae-Hwan Kim

  4. Department of Medicine, Division of Rheumatology, Eulji University Hospital, Daejeon, Republic of Korea

    Seung-Cheol Shim

  5. Department of Medicine/Rheumatology, Cedars-Sinai Medical Center, Los Angeles, California, USA

    Michael Weisman

  6. National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Michael Ward

  7. Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston, Houston, Texas, USA

    Xiaodong Zhou & John D Reveille

  8. Institut Cochin, Université Paris–Descartes, Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherhce (UMR) 8104, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France

    Henri-Jean Garchon, Gilles Chiocchia & Maxime Breban

  9. Division of Rheumatology, Ambroise Paré Hospital, Assistance Publique–Hôpitaux de Paris, Versailles-Saint-Quentin en Yvelines University, Boulogne-Billancourt, France

    Henri-Jean Garchon & Maxime Breban

  10. University Hospital North Norway, Tromso, Norway

    Johannes Nossent

  11. Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia

    Johannes Nossent

  12. Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway

    Benedicte A Lie

  13. Department of Immunology, Oslo University Hospital, Oslo, Norway

    Benedicte A Lie

  14. Department of Rheumatology, University Hospital Oslo, Oslo, Norway

    Øystein Førre

  15. Centre for Vascular Prevention, Danube-University Krems, Krems, Austria

    Jaakko Tuomilehto

  16. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland

    Jaakko Tuomilehto

  17. King Abdulaziz University, Jeddah, Saudi Arabia

    Jaakko Tuomilehto

  18. Paijat-Hame Central Hospital, Lahti, Finland

    Kari Laiho

  19. Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China

    Lei Jiang, Yu Liu, Xin Wu & Huji Xu

  20. Department of Rheumatology, Ghent University Hospital, Ghent, Belgium

    Dirk Elewaut

  21. Department of Rheumatology, Hospital General de México, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, México

    Ruben Burgos-Vargas

  22. Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Simon Stebbings

  23. Division of Rheumatology, Toronto Western Hospital, Toronto, Ontario, Canada

    Nigil Haroon & Robert D Inman

  24. Queensland Institute of Medical Research, Royal Brisbane Hospital, Herston, Queensland, Australia

    Manuel A Ferreira

  25. Rheumatology Department, Hospital Puerta de Hierro, Madrid, Spain

    Juan Mulero

  26. Rheumatology Department, Complejo Hospitalario La Coruña, Instituto de Investigación Biomédica A Coruña (INIBIC), La Coruña, Spain

    Jose Luis Fernandez-Sueiro

  27. Rheumatology Department, Hospital Marqués de Valcecilla, Instituto de Formación e Investigación Marqués de Valcecillas (IFIMAV), Santander, Spain

    Miguel A Gonzalez-Gay

  28. Department of Immunology, Asturias Central University Hospital, Oviedo, Spain

    Carlos Lopez-Larrea

  29. Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain

    Carlos Lopez-Larrea

  30. Wellcome Trust Sanger Institute, Cambridge, UK

    Panos Deloukas

  31. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Peter Donnelly

  32. Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK

    Karl Gafney

  33. Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

    Hill Gaston

  34. Division of Rheumatology, University of Toronto, Toronto, Ontario, Canada

    Dafna D Gladman

  35. Toronto Western Research Institute, Toronto, Ontario, Canada

    Dafna D Gladman

  36. Psoriatic Arthritis Program, University Health Network, Toronto, Ontario, Canada

    Dafna D Gladman

  37. Memorial University of Newfoundland, St. John's, Newfoundland, Canada

    Proton Rahman

  38. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    Walter P Maksymowych

  39. Department of Medical Microbiology and Infection Control, Laboratory of Immunogenetics, VU University Medical Center, Amsterdam, The Netherlands

    J Bart A Crusius

  40. Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands

    Irene E van der Horst-Bruinsma

  41. Department of Medicine, Division of Allergy, Immunology, Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan

    Chung-Tei Chou

  42. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Chung-Tei Chou

  43. Division of Rheumatology, Spondyloarthropathy Group, Hospital Militar Central, Universidad de La Sabana, Bogotá, Colombia.,

    Raphael Valle-Oñate & Consuelo Romero-Sánchez

  44. Helgelandssykehuset, Mo i Rana, Norway

    Inger Myrnes Hansen

  45. Chronic Diseases Research Centre (CEDOC), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal

    Fernando M Pimentel-Santos

  46. Department of Laboratory Medicine, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway

    Vibeke Videm

  47. Department of Immunology and Transfusion Medicine, Trondheim University Hospital, Trondheim, Norway

    Vibeke Videm

  48. Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain

    Javier Martin

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

    David M Evans

Consortia

International Genetics of Ankylosing Spondylitis Consortium (IGAS)

  • Adrian Cortes
  • , Johanna Hadler
  • , Jenny P Pointon
  • , Philip C Robinson
  • , Tugce Karaderi
  • , Paul Leo
  • , Katie Cremin
  • , Karena Pryce
  • , Jessica Harris
  • , Seunghun Lee
  • , Kyung Bin Joo
  • , Seung-Cheol Shim
  • , Michael Weisman
  • , Michael Ward
  • , Xiaodong Zhou
  • , Henri-Jean Garchon
  • , Gilles Chiocchia
  • , Johannes Nossent
  • , Benedicte A Lie
  • , Øystein Førre
  • , Jaakko Tuomilehto
  • , Kari Laiho
  • , Lei Jiang
  • , Yu Liu
  • , Xin Wu
  • , Linda A Bradbury
  • , Dirk Elewaut
  • , Ruben Burgos-Vargas
  • , Simon Stebbings
  • , Louise Appleton
  • , Claire Farrah
  • , Jonathan Lau
  • , Tony J Kenna
  • , Nigil Haroon
  • , Manuel A Ferreira
  • , Jian Yang
  • , Juan Mulero
  • , Jose Luis Fernandez-Sueiro
  • , Miguel A Gonzalez-Gay
  • , Carlos Lopez-Larrea
  • , Panos Deloukas
  • , Peter Donnelly
  • , Australo-Anglo-American Spondyloarthritis Consortium (TASC)
  • , Groupe Française d'Etude Génétique des Spondylarthrites (GFEGS)
  • , Nord-Trøndelag Health Study (HUNT)
  • , Spondyloarthritis Research Consortium of Canada (SPARCC)
  • , Wellcome Trust Case Control Consortium 2 (WTCCC2)
  • , Paul Bowness
  • , Karl Gafney
  • , Hill Gaston
  • , Dafna D Gladman
  • , Proton Rahman
  • , Walter P Maksymowych
  • , Huji Xu
  • , J Bart A Crusius
  • , Irene E van der Horst-Bruinsma
  • , Chung-Tei Chou
  • , Raphael Valle-Oñate
  • , Consuelo Romero-Sánchez
  • , Inger Myrnes Hansen
  • , Fernando M Pimentel-Santos
  • , Robert D Inman
  • , Vibeke Videm
  • , Javier Martin
  • , Maxime Breban
  • , John D Reveille
  • , David M Evans
  • , Tae-Hwan Kim
  • , Bryan Paul Wordsworth
  •  & Matthew A Brown

Contributions

J. Hadler, K.C., K.P. and J. Harris performed genotyping. A.C., P.C.R., T.K., P.L., J.Y., M.A.B. and D.M.E. performed statistical analyses. J.P.P., S.L., K.B.J., S.-C.S., M. Weisman, M. Ward, X.Z., H.-J.G., G.C., J.N., B.A.L., Ø.F., J.T., K.L., L.J., Y.L., X.W., L.A.B., D.E., R.B.-V., S.S., L.A., C.F., J.L., N.H., J. Mulero, J.L.F.-S., M.A.G.-G., C.L.-L., P. Deloukas, P. Donnelly, P.B., K.G., H.G., D.D.G., P.R., W.P.M., H.X., J.B.A.C., I.E.v.d.H.-B., C.-T.C., R.V.-O., C.R.-S., I.M.H., F.M.P.-S., R.D.I., V.V., J. Martin, M.B., J.D.R. and T.-H.K. all contributed to subject recruitment and study design. A.C., M.A.B., D.M.E. and B.P.W. wrote the manuscript, and all authors contributed to manuscript drafting and reviewed the final manuscript. T.J.K. performed cell count and IL-6R studies in ankylosing spondylitis cases and controls. M.A.F. performed GWAS of cell counts in controls.

Corresponding author

Correspondence to Matthew A Brown.

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Competing interests

The author declare no competing financial interests.

Additional information

Details appear in the Supplementary Note.

Details appear in the Supplementary Note.

Details appear in the Supplementary Note.

Details appear in the Supplementary Note.

Details appear in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–11, Supplementary Figures 1–12, Supplementary Note (PDF 13979 kb)

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International Genetics of Ankylosing Spondylitis Consortium (IGAS). Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 45, 730–738 (2013). https://doi.org/10.1038/ng.2667

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