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

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.

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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.

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Correspondence to Matthew A Brown.

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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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