Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

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Abstract

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

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Figure 1: SNP association plots for ankylosing spondylitis–associated regions.

References

  1. 1

    Braun, J. et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum. 41, 58–67 (1998).

  2. 2

    Calin, A., Marder, A., Becks, E. & Burns, T. Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls. Arthritis Rheum. 26, 1460–1464 (1983).

  3. 3

    van der Linden, S., Valkenburg, H. & Cats, A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study. Br. J. Rheumatol. 22, 18–19 (1983).

  4. 4

    Brown, M.A. et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 40, 1823–1828 (1997).

  5. 5

    Brown, M.A., Laval, S.H., Brophy, S. & Calin, A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 59, 883–886 (2000).

  6. 6

    WTCCC & TASC. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

  7. 7

    Laval, S.H. et al. Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci. Am. J. Hum. Genet. 68, 918–926 (2001).

  8. 8

    Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  9. 9

    Goto, Y., Tanji, H., Hattori, A. & Tsujimoto, M. Glutamine-181 is crucial in the enzymatic activity and substrate specificity of human endoplasmic-reticulum aminopeptidase-1. Biochem. J. 416, 109–116 (2008).

  10. 10

    Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

  11. 11

    Kugathasan, S. et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat. Genet. 40, 1211–1215 (2008).

  12. 12

    Mielants, H. et al. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J. Rheumatol. 22, 2273–2278 (1995).

  13. 13

    Taft, R.J. et al. Tiny RNAs associated with transcription start sites in animals. Nat. Genet. 41, 572–578 (2009).

  14. 14

    Cui, X., Rouhani, F.N., Hawari, F. & Levine, S.J. Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J. Immunol. 171, 6814–6819 (2003).

  15. 15

    Cui, X. et al. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J. Clin. Invest. 110, 515–526 (2002).

  16. 16

    Lappalainen, M. et al. Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population. Inflamm. Bowel Dis. 14, 1118–1124 (2008).

  17. 17

    Waschke, K.A. et al. Tumor necrosis factor receptor gene polymorphisms in Crohn′s disease: association with clinical phenotypes. Am. J. Gastroenterol. 100, 1126–1133 (2005).

  18. 18

    Armaka, M. et al. Mesenchymal cell targeting by TNF as a common pathogenic principle in chronic inflammatory joint and intestinal diseases. J. Exp. Med. 205, 331–337 (2008).

  19. 19

    van der Linden, S., Valkenburg, H.A. & Cats, A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 27, 361–368 (1984).

  20. 20

    Timpson, N.J. et al. Common variants in the region around Osterix are associated with bone mineral density and growth in childhood. Hum. Mol. Genet. 18, 1510–1517 (2009).

  21. 21

    Price, A.L. et al. Long-range LD can confound genome scans in admixed populations. Am. J. Hum. Genet. 83, 132–135 author reply 135–139 (2008).

  22. 22

    Kiiveri, H. A Bayesian approach to variable selection when the number of variables is very large. in Science and Statistics: A Festschrift for Terry Speed vol. 40 (ed. Goldstein, D.R.) 127–143 (Institute of Mathematical Statistics. Beachwood, Ohio, USA, 2003).

  23. 23

    Willer, C.J. et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

  24. 24

    Lusa, L., Gentleman, R. & Ruschhaupt, M. GeneMeta: MetaAnalysis for High Throughput Experiments. R package version 1.16.0. (2008).

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Acknowledgements

We would like to thank all participants, with and without ankylosing spondylitis, who provided the case and control DNA and clinical information necessary for this study. We are also very grateful for the invaluable support received from the National Ankylosing Spondylitis Society (UK) and Spondyloarthritis Association of America in subject recruitment. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them and the whole Avon Longitudinal Study of Parents And Children (ALSPAC) team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. This study was funded by US 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 Award grant UL1RR024188, Cedars-Sinai General Clinical Research Center grant MO1-RR00425, Intramural Research Program of NIAMS/National Institutes of Health, and Rebecca Cooper Foundation (Australia). This study was funded in part by the Arthritis Research Campaign (UK), by the Wellcome Trust (grant number 076113) and by the Oxford Radcliffe Hospital Biomedical Research Centre ankylosing spondylitis chronic disease cohort (theme code A91202). M.A.B. is funded by the National Health and Medical Research Council (Australia). The UK Medical Research Council, the Wellcome Trust and the University of Bristol provide core support for ALSPAC.

Author information

Case assessment and recruitment: L.A.B., M.A.B., J.C.D., L.D., C.F., R.D.I., W.P.M., R.M., E.P., J.D.R., L.S., M.A.S., M.M.W., M.H.W. and B.P.W. Sample processing and genotyping: L.H.A., P.D., T.D., A.D., E.L.D., J.H., D.H., R.J., T.K., R.M., J.J.P., E.P., K.P., A.-M.S., J.T. and X.Z. Gene expression studies: R.D., E.G. and G.P.T. Data analysis: M.A.B., P.D., D.M.E. and P.L. Study design and management committee: M.A.B., J.D.R., M.M.W., M.H.W. and B.P.W. Manuscript preparation: M.A.B., D.M.E., P.L., J.D.R., M.A.S., M.H.W. and B.P.W. ALSPAC control data: P.D., V.K., L.P., S.M.R. and P.W.

Correspondence to John D Reveille or Matthew A Brown.

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Competing interests

M.A.B. is an employee of the University of Queensland, which has applied for patents relating to genes discovered in this study.

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Supplementary Figures 1–5 and Supplementary Tables 1–3 (PDF 731 kb)

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