Genomewide Screens in Ankylosing Spondylitis

  • Matthew A. Brown
Part of the Advances in Experimental Medicine and Biology book series (volume 649)


Efforts to identify genes other than HLA-B27 in AS have been driven by the strength of the evidence from genetic epidemiology studies indicating that HLA-B27, although a major gene in AS, is clearly not the only significant gene operating. This is the case for both genetic determinants of disease-susceptibility and phenotypic characteristics such as disease severity and associated disease features. In this chapter the genetic epidemiology of AS and the gene-mapping studies performed to date will be reviewed and the future direction of research in this field discussed.


Major Histocompatibility Complex Ankylose Spondylitis Major Histocompatibility Complex Class Bath Ankylose Spondylitis Disease Activity Index Major Histocompatibility Complex Gene 
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  1. 1.
    Taurog JD, Richardson JA, Croft JT et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994; 180(6):2359–64.PubMedCrossRefGoogle Scholar
  2. 2.
    Brown MA, Kennedy LG, MacGregor AJ et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA and the environment. Arthritis Rheum 1997;40(10):1823–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Pedersen O, Svendsen A, Ejstrup L et al. Heritability estimates on ankylosing spondylitis. Clin Exp Rheumatol 2006; 24(4):463.Google Scholar
  4. 4.
    Brown MA, Brophy S, Bradbury L et al. Identification of major loci controlling clinical manifestations of ankylosing spondylitis. Arthritis Rheum 2003; 48(8):2234–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Hamersma J, Cardon LR, Bradbury L et al. Is disease severity in ankylosing spondylitis genetically determined? Arthritis Rheum 2001; 44(6):1396–400.PubMedCrossRefGoogle Scholar
  6. 6.
    Brophy S, Hickey S, Menon A et al. Concordance of disease severity among family members with ankylosing spondylitis? J Rheumatol 2004; 31(9):1775–8.PubMedGoogle Scholar
  7. 7.
    Rowland-Jones S, Colbert RA, Dong T et al. Distinct recognition of closely-related HIV-1 and HIV-2 cytotoxic T-cell epitopes presented by HLA-B*2703. AIDS 1998; 12(11):1391–3.PubMedCrossRefGoogle Scholar
  8. 8.
    Risch N. Linkage strategies for genetically complex traits I. Multilocus models. Am J Hum Genet 1990; 46(2):222–8.PubMedGoogle Scholar
  9. 9.
    Brown MA, Laval SH, Brophy S et al. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000; 59(11):883–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Lander ES, Botstein D., Strategies for studying heterogeneous genetic traits in humans by using a linkage map of restriction fragment length polymorphisms. Proc Natl Acad Sci USA 1986; 83(19):7353–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Hugor JP, Chamaillard M, Zouali H et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001; 411(6837):599–603.CrossRefGoogle Scholar
  12. 12.
    Laurin N, Brown JP, Morissette J et al. Recurrent mutation fo the gene encoding sequesstosome 1 (SQSTM1/p62) in Paget disease of bone. Am J Hum Genet 2002; 70(6):1582–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Ferrari SL, Deutsch S, Choudhury U et al. Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size and stature in whites. Am J Hum Genet 2004; 74(5):866–75.PubMedCrossRefGoogle Scholar
  14. 14.
    Koay M, Woon P-Y, Zhuang Y et al. Influence of LRP5 polymorphisms on normal variation in BMD. Journal of Bone and Mineral Research 2004; 19(10):1619–1627.PubMedCrossRefGoogle Scholar
  15. 15.
    Little R, Carulli J, Del Mastro R et al. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002; 70:11–19.PubMedCrossRefGoogle Scholar
  16. 16.
    Consortium WTCC. Genomewide association study of 14,000 cases of seven common diseases and 3000 controls. Nature 2007; 447:661–83.CrossRefGoogle Scholar
  17. 17.
    Zhang G, Luo J, Bruckel J et al. Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis Rheum 2004; 50(7):2246–54.PubMedCrossRefGoogle Scholar
  18. 18.
    Miceli-Richard C, Zouali H, Said-Nahal R et al. Significant linkage to spondyloarthropathy on 9q31-34. Hum Mol Genet 2004; 13(15):1641–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Laval SH, Timms A, Edwards S et al. Whole-genome screening in ankylosing spondylitis: evidence of nonMHC genetic-susceptibility loci. Am J Hum Genet 2001; 68(4):918–26.PubMedCrossRefGoogle Scholar
  20. 20.
    Brown MA, Pile KD, Kennedy LG et al. A genome-wide screen for susceptibility loci in ankylosing spondylitis. Arthritis Rheum 1998; 41(4):588–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Carter KW, Pluzhnikov A, Timms AE et al. Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis. Rheumatology (Oxford) 2007; 46(5):763–71.CrossRefGoogle Scholar
  22. 22.
    Timms AE, Crane AM, Sims AM et al. The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis. Am J Hum Genet 2004; 75(4):587–95.PubMedCrossRefGoogle Scholar
  23. 23.
    van der Paardt M, Crusius JB, Garcia-Gonzalez MA et al. Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatology (Oxford) 2001; 41(12):1419–23.CrossRefGoogle Scholar
  24. 24.
    McGarry F, Neilly J, Anderson N et al. A polymorphism within the interleukin 1 receptor antagonist (IL-1Ra) gene is associated with ankylosing spondylitis. Rheumatology (Oxford) 2001; 40 12):1359–64.CrossRefGoogle Scholar
  25. 25.
    Chou CT, Timms AE, Wei JC et al. Replication of association of IL1 gene complex members with ankylosing spondylitis in taiwanese chinese. Ann Rheum Dis 2006; 65(8):1106–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Brown MA, Edwards S, Hoyle E et al. Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis. Hum Mol Genet 2000; 9(11):1563–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Beyeler C, Armstrong M, Bird HA et al. Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 1996; 55(1):66–8.PubMedCrossRefGoogle Scholar
  28. 28.
    WTCCC, TASC. A genome-wide scan of 14,000 nonsynonymous coding SNPs in 5,500 individuals: The Wellcome Trust Case Control Consortium. Nat Genet 2007; 39(11):1329–37.CrossRefGoogle Scholar
  29. 29.
    Park H, Li Z, Yang XO et al. A distinct lineage of CD4 T-cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6(11):1133–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Cua DJ, Sherlock J, Chen Y et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421(6924):744–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Murphy CA, Langrish CL, Chen Y et al. Divergent pro-and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198(12):1951–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Duerr RH, Taylor KD, Brant SR et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314(5804):1461–3.PubMedCrossRefGoogle Scholar
  33. 33.
    Tremelling M, Cummings F, Fisher SA et al. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology 2007; 132(5):1657–1664.PubMedCrossRefGoogle Scholar
  34. 34.
    Cargill M, Schrodi S, Chang M et al. A large-scale genetic assocation study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007; 80(2): 273–290.PubMedCrossRefGoogle Scholar
  35. 35.
    Reveille JD, Zhou X, McGinnis R et al. Interleukin-23 receptor polymorphisms are a major determinant of susceptibility to ankylosing spondylitis. Nat Genet 2007; Submitted.Google Scholar
  36. 36.
    de Vlam K, Mielants H, Cuvelier C et al. Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HlA association. J Rheumatol 2000; 27(12):2860–5.PubMedGoogle Scholar
  37. 37.
    Palm O, Moum B, Ongre A et al. Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study). J Rheumatol 2002; 29(3):511–5.PubMedGoogle Scholar
  38. 38.
    Salvarani C, Vlachonikolis IG, van der Heijde DM et al. Musculoskeletal manifestations in a population-based cohort of inflammatory bowel disease patients. Scand J Gastroenterol 2001; 3612):1307–13.PubMedCrossRefGoogle Scholar
  39. 39.
    Scarpa R, del Puente A, D’Arienzo A et al. The arthritis of ulcerative colitis: clinical and genetic aspects. J Rheumatol 1992: 19(3):373–7.PubMedGoogle Scholar
  40. 40.
    Steer S, Jones H, Hibbert J et al. Low back pain, sacroiliitis and the relationship with HLA-B27 in Crohn’s disease. J Rheumatol 2003; 30(3):518–22.PubMedGoogle Scholar
  41. 41.
    Thjodleifsson B, Geirsson AJ, Bjornsson S et al. A common genetic background for inflammatory bowel disease and ankylosing spondylitis: a genealogic study in Iceland. Arthritis Rheum 2007; 56(8):2633–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Hammer GE, Gonzalez F, Champsaur M et al. The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. Nat Immunol 2006; 7(1):103–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Kanaseki T, Blanchard N, Hammer GE et al. ERAAP synergizes with MHC class I molecules to make the final cut in the antigenic peptide precursors in the endoplasmic reticulum. Immunity 2006; 25(5):795–806.PubMedCrossRefGoogle Scholar
  44. 44.
    Cui X, Rouhani FN, Hawari F et al. Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J Immunol 2003; 171(12):6814–9.PubMedGoogle Scholar
  45. 45.
    Cui X, Rouhani FN, Hawari F et al. An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding. J Biol Chem 2003; 278(31):28677–85.PubMedCrossRefGoogle Scholar
  46. 46.
    Cui X, Hawari F, Alsaaty S et al. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J Clin Invest 2002; 110(4):515–26.PubMedGoogle Scholar
  47. 47.
    Vazquez-Del MM, Garcia-Gonzalez A, Munoz-Valle JF et al. Interleukin 1beta (IL-1beta), IL-10, tumor necrosis factor-alpha and cellular proliferation index in peripheral blood mononuclear cells in patients with ankylosing spondylitis. J Rheumatol 2002; 29(3):522–6.Google Scholar
  48. 48.
    Maksymowych WP, Rahman P, Reeve JP et al. Association of the IL1 gene cluster with susceptibility to ankylosing spondylitis: an analysis of three canadian populations. Arthritis Rheum 2006; 54(3):974–85.PubMedCrossRefGoogle Scholar
  49. 49.
    Rahman P, Sun S, Peddle L et al. Assocation between the interleukin-1 family gene cluster and psoriatic arthritis. Arthritis Rheum 2006; 54(7):2321–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Sims A-M, Timms A, Bruges Armas J et al. Prospective meta-analysis of IL-1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis 2007; Submitted.Google Scholar
  51. 51.
    Timms AE, Zhang Y, Bradbury L et al. Investigation of the role of ANKH in ankylosing spondylitis. Arthritis Rheum 2003; 48(10):2898–902.PubMedCrossRefGoogle Scholar
  52. 52.
    Tsui FW, Tsui HW, Cheng EY et al. Novel genetic markers in the 5′-flanking region of ANKH are associated with ankylosing spondylitis. Arthritis Rheum 2003; 48(3):791–7.PubMedCrossRefGoogle Scholar
  53. 53.
    Adam R, Sturrock RD, Gracie JA. TLR4 mutations (Asp 299Gly and Thr399Ile) are not associated with ankylosing spondylitis. Ann Rheum Dis 2006; 65(8):1099–101.PubMedCrossRefGoogle Scholar
  54. 54.
    Gergely P Jr, Blazsek A, Weiszhar Z et al. Lack of genetic association of the Toll-like receptor 4 (TLR4) Asp299Gly and Thr399Ile polymorphisms with spondylarthropathies in a Hungarian population. Rheumatology (Oxford) 2006; 45(10):1194–6.CrossRefGoogle Scholar
  55. 55.
    Snelgrove T, Lim S, Greenwood C et al. Association of toll-like receptor 4 variants and ankylosing spondylitis: a case-control study. J Rheumatol 2007; 34(2):368–70.PubMedGoogle Scholar
  56. 56.
    van der Paardt M, Crusius JB, de Koning MH et al. No evidence for involvement of the Toll-like receptor 4 (TLR4) A896G and CD14-C260T polymorphisms in susceptibility to ankylosing spondylitis. Ann Rheum Dis 2005; 64(2):235–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Crane AM, Bradbury L, van Heel DA et al. Role of NOD2 variants in spondylarthritis. Arthritis Rheum 2002; 46(6):1629–33.PubMedCrossRefGoogle Scholar
  58. 58.
    Miceli-Richard C, Zouali H, Lesage S et al. CARD15/NOD2 analyses in spondylarthropathy. Arthritis Rheum 2002; 46(5):1405–6.PubMedCrossRefGoogle Scholar
  59. 59.
    van der Paardt M, Cruisusi JB, de Koning MH et al. CARD15 gene mutations are not associated with ankylosing spondylitis. Genes Immun 2003; 4(1):77–8.PubMedCrossRefGoogle Scholar
  60. 60.
    van Heel DA, McGovern DP, Cardon LR et al. Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics. Am J Med Genet 2002; 111(3):253–9.PubMedCrossRefGoogle Scholar
  61. 61.
    van Heel DA, Dechairo BM, Dawson G et al. The IBD6 Crohn’s disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants. Hum Mol Genet 2003; 12(20):2569–75.PubMedCrossRefGoogle Scholar
  62. 62.
    D’Amato M. The Crohn’s associated NOD2 3020InsC frameshift mutation does not confer susceptibility to ankylosing spondylitis. J Rheumatol 2002; 29(11):2470–1.PubMedGoogle Scholar
  63. 63.
    Ferreiros-Vidal I, Amarelo J, Barros F et al. Lack of association of ankylosing spondylitis with the most common NOD2 susceptibility alleles to Crohn’s disease. J Rheumatol 2003; 30(1):102–4.PubMedGoogle Scholar
  64. 64.
    Peeters H, Vander Cruyssen B, Laukens D et al. Radiological sacroilitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn’s disease. Ann Rheum Dis 2004; 63(9):1131–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Kim TH, Rahman P, Jun JB et al. Analysis of CARD15 polymorphisms in Korean patients with ankylosing spondylitis reveals absence of common variants seen in western populations. J Rheumatol 2004; 31(10):1959–61.PubMedGoogle Scholar
  66. 66.
    Lopez-Larrea C, Blanco-Gelaz MA, Torre-Alonso JC et al. Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations. Arthritis Res Ther 2006; 8(4):R101.PubMedCrossRefGoogle Scholar
  67. 67.
    Brown MA, Pile KD, Kennedy LG et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis 1996; 55(4):268–70.PubMedCrossRefGoogle Scholar
  68. 68.
    Robinson WP, van der Linden SM, Khan MA et al. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum 1989; 32(9):1135–41.PubMedCrossRefGoogle Scholar
  69. 69.
    Wei JC, Tsai WC, Lin HS et al. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology (Oxford) 2004; 43(7):839–42.CrossRefGoogle Scholar
  70. 70.
    Brown MA, Kennedy LG, Darke C et al. The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis. Arthritis Rheum 1998; 41(3):460–5.PubMedCrossRefGoogle Scholar
  71. 71.
    Ploski R, Maksymowych W, Forre O. HLA-DR8 and susceptibility to acute anterior uveitis in ankylosing spondylitis: comment on the article by Monowarul Islam et al. Arthritis Rheum 1996; 39(2):351–2.PubMedCrossRefGoogle Scholar
  72. 72.
    Monowarul ISlam SM, Numaga J, Fujino Y et al. HLA-DR8 and acute anterior uveitis in ankylosing spondylitis. Arthritis Rheum 1995; 38(4):547–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Sims AM, Wordsworth BP, Brown MA. Genetic susceptibility to ankylosing spondylitis. Curr Mol Med 2004 4(1):13–20.PubMedCrossRefGoogle Scholar
  74. 74.
    D’Amato M, Fiorillo MT, Carcassi C et al. Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol 1995; 25(11):3199–201.PubMedCrossRefGoogle Scholar
  75. 75.
    Sims AM, Barnardo M, Herzberg I et al. Non B27 MHC associations of ankylosing spondylitis. Genes Immun 2007; 8(2):115–23.PubMedCrossRefGoogle Scholar
  76. 76.
    Miettinen OS. Proportion of disease caused or prevented by a given exposure, trait or intervention. Am J Epidemiol 1974; 99 (5):325–32.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Matthew A. Brown
    • 1
    • 2
  1. 1.Diamantina Institute of Cancer, Immunology and Metabolic MedicinePrincess Alexandra HospitalWooloongabbaAustralia
  2. 2.Botnar Research Center Nuffield Orthopaedic CenterUniversity of Oxford Institute of Musculoskeletal SciencesOxfordUK

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