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