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Non-B27 MHC associations of ankylosing spondylitis

Genes & Immunity volume 8, pages 115–123 (2007)Cite this article

Abstract

Ankylosing spondylitis (AS) has been associated with human leukocyte antigen (HLA)-B27 for over 30 years; however, the mechanism of action has remained elusive. Although many studies have reported associations between AS and other genes in the major histocompatibility complex (MHC) in AS, no conclusive results have emerged. To investigate the contribution of non-B27 MHC genes to AS, a large cohort of AS families and controls were B27 typed and genotyped across the region. Interrogation of the data identified a region of 270 kb, lying from 31 952 649 to 32 221 738 base pairs from the p-telomere of chromosome 6 and containing 23 genes, which is likely to include genes involved with susceptibility to AS.

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References

  1. Caffrey MF, James DC . Human lymphocyte antigen association in ankylosing spondylitis. Nature 1973; 242: 121.

    Article  CAS  PubMed  Google Scholar 

  2. Schlosstein L, Terasaki PI, Bluestone R, Pearson C . High association of an HL-A antigen W27, with ankylosing spondylitis. N Engl J Med 1973; 288: 704–705.

    Article  CAS  PubMed  Google Scholar 

  3. Brewerton DA, Hart FD, Nicholls A, Caffrey M, James DC, Sturrock RD . Ankylosing spondylitis and HL-A 27. Lancet 1973; 1: 904–907.

    Article  CAS  PubMed  Google Scholar 

  4. Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997; 40: 1823–1828.

    Article  CAS  PubMed  Google Scholar 

  5. Braun J, Bollow M, Remlinger G, Eggens U, Rudwaleit M, Distler A et al. Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors. Arthritis Rheum 1998; 41: 58–67.

    Article  CAS  PubMed  Google Scholar 

  6. Gran JT, Husby G, Hordvik M . Prevalence of ankylosing spondylitis in males and females in a young middle-aged population of Tromso, northern Norway. Ann Rheum Dis 1985; 44: 359–367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. van der Linden SM, Valkenburg HA, de Jongh BM, Cats A . The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population. Arthritis Rheum 1984; 27: 241–249.

    Article  CAS  PubMed  Google Scholar 

  8. Brown MA, Laval SH, Brophy S, Calin A . Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000; 59: 883–886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brown MA, Pile KD, Kennedy GL, Campbell D, Andrew L, March R et al. A genome-wide screen for susceptibility loci in ankylosing spondylitis. Arthritis Rheum 1998; 41: 588–595.

    Article  CAS  PubMed  Google Scholar 

  10. Laval SH, Timms A, Edwards S, Bradbury L, Brophy S, Milicic A et al. Whole-genome screening in ankylosing spondylitis: evidence of non-MHC genetic-susceptibility loci. Am J Hum Genet 2001; 68: 918–926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Miceli-Richard C, Zouali H, Said-Nahal R, Lesage S, Merlin F, De Toma C et al. Significant linkage to spondyloarthropathy on 9q31–34. Hum Mol Genet 2004; 13: 1641–1648.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang G, Luo J, Bruckel J, Weisman MA, Schumacher HR, Khan MA et al. Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis Rheum 2004; 50: 2246–2254.

    Article  CAS  PubMed  Google Scholar 

  13. Breur-Vriesendorp BS, de-Waal LP, Ivanyi P . Different linkage disequilibria of HLA-B27 subtypes and HLA-C locus alleles. Tissue Antigens 1988; 32: 74–77.

    Article  CAS  PubMed  Google Scholar 

  14. Gonzalez-Roces S, Brautbar C, Pena M, Dominguez O, Coto E, Alvarez V et al. Molecular analysis of HLA-B27 haplotypes in Caucasoids. Frequencies of B27-Cw in Jewish and Spanish populations. Hum Immunol 1994; 41: 127–134.

    Article  CAS  PubMed  Google Scholar 

  15. Lopez-Larrea C, Gonzalez-Roces S, Pena M, Dominguez O, Coto E, Alvarez V et al. Characterization of B27 haplotypes by oligotyping and genomic sequencing in the Mexican Mestizo population with ankylosing spondylitis: juvenile and adult onset. Hum Immunol 1995; 43: 174–180.

    Article  CAS  PubMed  Google Scholar 

  16. Robinson WP, van der Linden SM, Khan MA, Rentsch HU, Cats A, Russell A et al. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+patients. Arthritis Rheum 1989; 32: 1135–1141.

    Article  CAS  PubMed  Google Scholar 

  17. Rubin LA, Amos CI, Wade JA, Martin JR, Bale SJ, Little AH et al. Investigating the genetic basis for ankylosing spondylitis. Linkage studies with the major histocompatibility complex region. Arthritis Rheum 1994; 37: 1212–1220.

    Article  CAS  PubMed  Google Scholar 

  18. Brown MA, Pile KD, Kennedy LG, Calin A, Darke C, Bell J et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom. Ann Rheum Dis 1996; 55: 268–270.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tsuchiya N, Shiota M, Moriyama S, Ogawa A, Komatsu-Wakui M, Mitsui H et al. MICA allele typing of HLA-B27 positive Japanese patients with seronegative spondylarthropathies and healthy individuals: differential linkage disequilibrium with HLA-B27 subtypes. Arthritis Rheum 1998; 41: 68–73.

    Article  CAS  PubMed  Google Scholar 

  20. Yabuki K, Ota M, Goto K, Kimura T, Nomura E, Ohno S et al. Triplet repeat polymorphism in the MICA gene in HLA-B27 positive and negative Caucasian patients with ankylosing spondylitis. Hum Immunol 1999; 60: 83–86.

    Article  CAS  PubMed  Google Scholar 

  21. Martinez-Borra J, Gonzalez S, Lopez-Vazquez A, Gelaz MA, Armas JB, Kanga U et al. HLA-B27 alone rather than B27-related class I haplotypes contributes to ankylosing spondylitis susceptibility. Hum Immunol 2000; 61: 131–139.

    Article  CAS  PubMed  Google Scholar 

  22. Gonzalez S, Torre-Alonso JC, Martinez-Borra J, Fernandez Sanchez JA, Lopez-Vazquez A, Rodriguez Perez A et al. TNF-238A promoter polymorphism contributes to susceptibility to ankylosing spondylitis in HLA-B27 negative patients. J Rheumatol 2001; 28: 1288–1293.

    CAS  PubMed  Google Scholar 

  23. Hohler T, Kruger A, Schneider PM, Schopf RE, Knop J, Rittner C et al. A TNF-alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis (see comments). J Invest Dermatol 1997; 109: 562–565.

    Article  CAS  PubMed  Google Scholar 

  24. McGarry F, Walker R, Sturrock R, Field M . The −308.1 polymorphism in the promoter region of the tumor necrosis factor gene is associated with ankylosing spondylitis independent of HLA-B27. J Rheumatol 1999; 26: 1110–1116.

    CAS  PubMed  Google Scholar 

  25. Milicic A, Lindheimer F, Laval S, Rudwaleit M, Ackerman H, Wordsworth P et al. Interethnic studies of TNF polymorphisms confirm the likely presence of a second MHC susceptibility locus in ankylosing spondylitis. Genes Immun 2000; 1: 418–422.

    Article  CAS  PubMed  Google Scholar 

  26. Rudwaleit M, Siegert S, Yin Z, Eick J, Thiel A, Radbruch A et al. Low T cell production of TNFalpha and IFNgamma in ankylosing spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene polymorphism. Ann Rheum Dis 2001; 60: 36–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vargas-Alarcon G, Londono JD, Hernandez-Pacheco G, Pacheco-Tena C, Castillo E, Cardiel MH et al. Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in Mexican patients. Ann Rheum Dis 2002; 61: 714–717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Westman P, Partanen J, Leirisalo-Repo M, Koskimies S . HSP70-Hom NcoI polymorphism and HLA-associations in the Finnish population and in patients with ankylosing spondylitis or reactive arthritis. Eur J Immunogenet 1994; 21: 81–90.

    Article  CAS  PubMed  Google Scholar 

  29. Fraile A, Nieto A, Mataran L, Martin J . HSP70 gene polymorphisms in ankylosing spondylitis. Tissue Antigens 1998; 51 (4 Part 1): 382–385.

    CAS  PubMed  Google Scholar 

  30. Lin JA, Ye DF, Zhu YY, Chen JM, Zheng WQ . Relationship between heat shock protein 70-hom gene polymorphism and ankylosing spondylitis. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2004; 21: 182–183.

    CAS  PubMed  Google Scholar 

  31. Nahal R, Gautreau C, Amor B, Berthelot J-M, Combes B, Dougados M et al. Genetic investigation in familial spondyloarthropathy (SpA) with focus on HLA region using transmission desequilibrium test (TDT). Arthritis Rheum 1996; 39: S122.

    Google Scholar 

  32. Vargas-Alarcon G, Londono JD, Hernandez-Pacheco G, Gamboa R, Castillo E, Pacheco-Tena C et al. Heat shock protein 70 gene polymorphisms in Mexican patients with spondyloarthropathies. Ann Rheum Dis 2002; 61: 48–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brown MA, Kennedy LG, Darke C, Gibson K, Pile KD, Shatford JL et al. The effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis. Arthritis Rheum 1998; 41: 460–465.

    Article  CAS  PubMed  Google Scholar 

  34. Madhavan R, Parthiban M, Rajendran CP, Chandrasekaran AN, Zake L, Sanjeevi CB . HLA class I and class II association with ankylosing spondylitis in a Southern Indian population. Ann NY Acad Sci 2002; 958: 403–407.

    Article  CAS  PubMed  Google Scholar 

  35. Said-Nahal R, Miceli-Richard C, Gautreau C, Tamouza R, Borot N, Porcher R et al. The role of HLA genes in familial spondyloarthopathy: a comprehensive study of 70 multiplex families. Ann Rheum Dis 2002; 61: 201–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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: 351–352.

    Article  CAS  PubMed  Google Scholar 

  37. Maksymowych WP, Gorodezky C, Olivo A, Alaez C, Wong C, Burgos-Vargas R et al. HLA-DRB1*08 influences the development of disease in Mexican Mestizo with spondyloarthropathy. J Rheumatol 1997; 24: 904–907.

    CAS  PubMed  Google Scholar 

  38. Monowarul Islam SM, Numaga J, Fujino Y, Masuda K, Ohda H, Hirata R et al. HLA-DR8 and acute anterior uveitis in ankylosing spondylitis. Arthritis Rheum 1995; 38: 547–550.

    Article  CAS  PubMed  Google Scholar 

  39. Maksymowych WP, Tao S, Li Y, Wing M, Russell AS . Allelic variation at the TAP 1 locus influences disease phenotype in HLA-B27 positive individuals with ankylosing spondylitis. Tissue Antigens 1995; 45: 328–332.

    Article  CAS  PubMed  Google Scholar 

  40. Burney RO, Pile KD, Gibson K, Calin A, Kennedy LG, Sinnott PJ et al. Analysis of the MHC class II encoded components of the HLA class I antigen processing pathway in ankylosing spondylitis. Ann Rheum Dis 1994; 53: 58–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Westman P, Partanen J, Leirisalorepo M, Koskimies S . TAP1 and TAP2 polymorphism in HLA-B27-positive subpopulations – no allelic differences in ankylosing spondylitis and reactive arthritis. Hum Immunol 1995; 44: 236–242.

    Article  CAS  PubMed  Google Scholar 

  42. Fraile A, Collado MD, Mataran L, Martin J, Nieto A . TAP1 and TAP2 polymorphism in Spanish patients with ankylosing spondylitis. Exp Clin Immunogenet 2000; 17: 199–204.

    Article  CAS  PubMed  Google Scholar 

  43. Konno Y, Numaga J, Mochizuki M, Mitsui H, Hirata R, Maeda H . TAP polymorphism is not associated with ankylosing spondylitis and complications with acute anterior uveitis in HLA-B27-positive Japanese. Tissue Antigens 1998; 52: 478–483.

    Article  CAS  PubMed  Google Scholar 

  44. Maksymowych WP, Wessler A, Schmitt-Egenolf M, Suarez-Almazor M, Ritzel G, Von-Borstel RC et al. Polymorphism in an HLA linked proteasome gene influences phenotypic expression of disease in HLA-B27 positive individuals. J Rheumatol 1994; 21: 665–669.

    CAS  PubMed  Google Scholar 

  45. Maksymowych WP, Russell AS . Polymorphism in the LMP2 gene influences the relative risk for acute anterior uveitis in unselected patients with ankylosing spondylitis. Clin Invest Med 1995; 18: 42–46.

    CAS  PubMed  Google Scholar 

  46. Maksymowych WP, Suarez-Almazor M, Chou CT, Russell AS . Polymorphism in the LMP2 gene influences susceptibility to extraspinal disease in HLA-B27 positive individuals with ankylosing spondylitis. Ann Rheum Dis 1995; 54: 321–324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Maksymowych WP, Adlam N, Lind D, Russell AS . Polymorphism of the LMP2 gene and disease phenotype in ankylosing spondylitis: no association with disease severity. Clin Rheumatol 1997; 16: 461–465.

    Article  CAS  PubMed  Google Scholar 

  48. Maksymowych WP, Jhangri GS, Gorodezky C, Luong M, Wong C, Burgos-Vargas R et al. The LMP2 polymorphism is associated with susceptibility to acute anterior uveitis in HLA-B27 positive juvenile and adult Mexican subjects with ankylosing spondylitis. Ann Rheum Dis 1997; 56: 488–492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Maksymowych WP, Tao S, Vaile J, Suarez-Almazor M, Ramos-Remus C, Russell AS . LMP2 polymorphism is associated with extraspinal disease in HLA-B27 negative Caucasian and Mexican Mestizo patients with ankylosing spondylitis. J Rheumatol 2000; 27: 183–189.

    CAS  PubMed  Google Scholar 

  50. Ploski R, Flato B, Vinje O, Maksymowych W, Forre O, Thorsby E . Association to HLA-DRB1*08, HLA-DPB1*0301 and homozygosity for an HLA-linked proteasome gene in juvenile ankylosing spondylitis. Hum Immunol 1995; 44: 88–96.

    Article  CAS  PubMed  Google Scholar 

  51. Hohler T, Schaper T, Schneider PM, Krummenauer F, Rittner C, Meyer zum Buschenfelde KH et al. No primary association between LMP2 polymorphisms and extraspinal manifestations in spondyloarthropathies. Ann Rheum Dis 1997; 56: 741–743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Purcell S, Cherny SS, Sham PC . Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003; 19: 149–150.

    Article  CAS  PubMed  Google Scholar 

  53. Koeleman BP, Dudbridge F, Cordell HJ, Todd JA . Adaptation of the extended transmission/disequilibrium test to distinguish disease associations of multiple loci: the conditional extended transmission disequilibrium test. Ann Hum Genet 2000; 64 (Part 3): 207–213.

    Article  CAS  PubMed  Google Scholar 

  54. Abecasis GR, Cardon LR, Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.

    Article  CAS  PubMed  Google Scholar 

  55. Yang Z, Mendoza AR, Welch TR, Zipf WB, Yu CY . Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. J Biol Chem 1999; 274: 12147–12156.

    Article  CAS  PubMed  Google Scholar 

  56. Brown MA, Brophy S, Bradbury L, Hamersma J, Timms A, Laval S et al. Identification of major loci controlling clinical manifestations of ankylosing spondylitis. Arthritis Rheum 2003; 48: 2234–2239.

    Article  PubMed  Google Scholar 

  57. Feldtkeller E, Khan MA, van der Heijde D, van der Linden S, Braun J . Age at disease onset and diagnosis delay in HLA-B27 negative vs positive patients with ankylosing spondylitis. Rheumatol Int 2003; 23: 61–66.

    Article  PubMed  Google Scholar 

  58. Jaakkola E, Herzberg I, Laiho K, Barnardo MC, Pointon JJ, Kauppi M et al. Finnish HLA studies confirm the increased risk conferred by HLA-B27 homozygosity in ankylosing spondylitis. Ann Rheum Dis 2006; 65: 775–780. Epub 2005 Oct 25.

    Article  CAS  PubMed  Google Scholar 

  59. Beyeler C, Armstrong M, Bird HA, Idle JR, Daly AK . Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 1996; 55: 66–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brown MA, Edwards S, Hoyle E, Campbell S, Laval S, Daly AK et al. Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis. Hum Mol Genet 2000; 9: 1563–1566.

    Article  CAS  PubMed  Google Scholar 

  61. Zweers MC, Hakim AJ, Grahame R, Schalkwijk J . Joint hypermobility syndromes: the pathophysiologic role of tenascin-X gene defects. Arthritis Rheum 2004; 50: 2742–2749.

    Article  CAS  PubMed  Google Scholar 

  62. van der Linden S, Valkenburg HA, Cats A . Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984; 27: 361–368.

    Article  CAS  PubMed  Google Scholar 

  63. Jaakkola E, Herzberg I, Crane AM, Pointon JJ, Laiho K, Kauppi M et al. A novel human leucocyte antigen-DRB1 genotyping method based on multiplex primer extension reactions. Tissue Antigens 2004; 64: 88–95.

    Article  CAS  PubMed  Google Scholar 

  64. Pusch W, Wurmbach JH, Thiele H, Kostrzewa M . MALDI-TOF mass spectrometry-based SNP genotyping. Pharmacogenomics 2002; 3: 537–548.

    Article  CAS  PubMed  Google Scholar 

  65. Wigginton JE, Abecasis GR . PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 2005; 21: 3445–3447.

    Article  CAS  PubMed  Google Scholar 

  66. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  PubMed  Google Scholar 

  67. Stephens M, Donnelly P . A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 2003; 73: 1162–1169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nyholt DR . A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 2004; 74: 765–769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kruglyak L, Daly MJ, Reeve Daly MP, Lander ES . Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 1996; 58: 1347–1363.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Abecasis GR, Cookson WO . GOLD – graphical overview of linkage disequilibrium. Bioinformatics 2000; 16: 182–183.

    Article  CAS  PubMed  Google Scholar 

  71. Terwilliger JD, Ott J . Handbook of Human Genetic Linkage. John Hopkins University Press: Baltimore, MD, USA, 1994.

    Google Scholar 

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Authors and Affiliations

  1. Botnar Research Centre, Nuffield Orthopaedic Centre, Oxford, UK

    A-M Sims, I Herzberg, L Bradbury, B P Wordsworth & M A Brown

  2. Oxford Transplant Centre, Churchill Hospital, Oxford, UK

    M Barnardo

  3. Royal National Hospital for Rheumatic Diseases, Bath, UK

    A Calin

  4. Welsh Blood Service, Pontyclun, UK

    C Darke

  5. Centre for Immunology and Cancer Research, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia

    A-M Sims, L Bradbury & M A Brown

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  1. A-M Sims
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  2. M Barnardo
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Correspondence to M A Brown.

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This work was funded by Arthritis Research Campaign, UK.

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Sims, AM., Barnardo, M., Herzberg, I. et al. Non-B27 MHC associations of ankylosing spondylitis. Genes Immun 8, 115–123 (2007). https://doi.org/10.1038/sj.gene.6364362

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