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An Update on the Genetic Polymorphism of HLA-B*27 With 213 Alleles Encompassing 160 Subtypes (and Still Counting)

  • Spondyloarthritis (M Khan, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This publication updates an earlier review on the ever increasing knowledge about genetic polymorphism of HLA-B*27 and discusses its clinical relevance.

Recent Findings

As of January 1, 2017, there are 213 known alleles of HLA-B*27 at nucleotide sequence level, while at the translated protein level, there are 160 known subtypes based on one or more amino acid sequence differences. Some of these subtypes exhibit differential association with ankylosing spondylitis, and there may even be some level of hierarchy in this regard. On the other hand, HLA-B*27 has a protective effect against HCV, and this effect is also influenced by some of the subtypes of HLA-B*27. This may have important implications for designing anti-viral vaccines for global population and also for developing individualized treatments and vaccines.

Summary

Disease association and disease protective roles of HLA-B*27 suggest a common ground, i.e., promoting a more pronounced immune/inflammatory response for effective clearance of some pathogens, but that might, on the other hand, lead to autoimmunity and tissue injury in some circumstances.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Robinson J, Halliwell JA, Hayhurst JD, et al. The IPD and IMGT/HLA database: allele variant databases. Nucleic Acids Res. 2015;43(Database issue):D423–31. doi:10.1093/nar/gku1161. This publication explains the Immuno Polymorphism Database (IPD) that was developed in 2003 to provide a centralized system for the study of polymorphism in genes of the immune system. The IPD project was established by the HLA Informatics Group.

    Article  PubMed  Google Scholar 

  2. •• Khan MA. Polymorphism of HLA-B27: 105 subtypes currently known. Curr Rheumatol Rep. 2013;15:362. doi:10.1007/s11926-013-0362-y. The author’s previous review of the subject that is worth reading for the current update and expansion of this subject.

    Article  PubMed  Google Scholar 

  3. Brewerton DA. Discovery: HLA and disease. Curr Opin Rheumatol. 2003;15(4):369–73.

    Article  PubMed  Google Scholar 

  4. • Khan MA. Ankylosing spondylitis - axial spondyloarthritis. Professional Communications Inc. (PCI). West Islip, NY. 2016, pp.1–333. ISBN: 978-1-943236-08-4. The most current book on AS/AxSpA published in September, 2016 that provides additional current information on HLA-B27 and its clinical utility as an aid to disease recognition.

  5. Khan MA. HLA and spondyloarthropathies. Chapter 16. In: Mehra NK, editor. The HLA complex in biology and medicine. A Resource Book. New Delhi: Jaypee Brothers Medical Publishers Ltd; 2010. p. 259–75.

    Google Scholar 

  6. •• Bowness P. HLA-B27. Annu Rev Immunol. 2015;33:29–48. An excellent and comprehensive review covering the role of HLA-B27 in etiopathogenesis of AS/AxSpA.

    Article  CAS  PubMed  Google Scholar 

  7. •• Ellinghaus D, Jostin L, Spain SL, et al. Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nat Genet. 2016;48(5):510–8. The authors report combined assessments of Immunochip genotyping datasets from 52,262 patients with five closely associated diseases (AS, Crohn’s disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis; all seronegative inflammatory diseases) and 34,213 healthy controls. They were able to delineate the genetic overlap between these conditions, identify 27 new associations, and highlights disease-specific patterns at shared loci.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lopez-Larrea C, Sujirachato K, Mehra NK, et al. HLA-B27 subtypes in Asian patients with ankylosing spondylitis: evidence for new associations. Tissue Antigens. 1995;45(3):169–76.

    Article  CAS  PubMed  Google Scholar 

  9. Nasution AR, Mardjuadi A, Kunmartini S, et al. HLA-B27 subtypes positively and negatively associated with spondyloarthropathy. J Rheumatol. 1997;24:1111–4.

    CAS  PubMed  Google Scholar 

  10. Diaz-Pena R, Lopez-Vazquez A, Lopez-Larrea C. Old and new HLA associations with ankylosing spondylitis. Tissue Antigens. 2012;80:205–13.

    Article  CAS  PubMed  Google Scholar 

  11. Van Gaalen FA. Does HLA-B*2706 protect against ankylosing spondylitis? A meta-analysis. Int J Rheum Dis. 2012;15(1):8–12.

    Article  PubMed  Google Scholar 

  12. 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;25:3199–201.

    Article  PubMed  Google Scholar 

  13. Khan MA, Mathieu A, Sorrentino R, Akkoc N. The pathogenetic role of HLA-B27 and its subtypes. Autoimmun Rev. 2007;6(3):183–9.

    Article  CAS  PubMed  Google Scholar 

  14. • Jeanty C, Sourisce A, Noteuil A, et al. HLA–B27 subtype oligomerization and intracellular accumulation patterns correlate with predisposition to spondyloarthritis. Arthritis Rheumatol. 2014;66(8):2113–23. This paper enhances our understanding of the pathogenic role of HLA-B27.

  15. Cheng X, Mei Y, Ji X, et al. Molecular mechanism of the susceptibility difference between HLA-B*27:02/04/05 and HLA-B*27:06/09 to ankylosing spondylitis: substitution analysis, MD simulation, QSAR modelling, and in vitro assay. SAR QSAR Environ Res. 2016;27(5):409–25.

    Article  CAS  PubMed  Google Scholar 

  16. Mou YK, Zhang PP, Li QX, et al. Changes of serum levels of MMP-3, sRANKL, and OPG in juvenile-onset ankylosing spondylitis patients carrying different HLA-B27 subtypes. Clin Rheumatol. 2015;34(6):1085–9.

    Article  PubMed  Google Scholar 

  17. •• Schittenhelm RB, Sivaneswaran S, Lim Kam Sian TC, et al. Human leukocyte antigen (HLA) B27 allotype-specific binding and candidate arthritogenic peptides revealed through heuristic clustering of Data-independent Acquisition Mass Spectrometry (DIA-MS) data. Mol Cell Proteomics. 2016;15(6):1867–76. The authors have identified 26 peptides, which are presented in lower abundance by HLA-B*27:06 and HLA-B*27:09 compared with disease-associated HLA-B27 subtypes. They point out that "although these differences were observed to be very subtle, these 26 peptides might encompass the sought-after arthritogenic peptide(s)".

    Article  CAS  PubMed  Google Scholar 

  18. Colbert RA, Tran TM, Layh-Schmitt G. HLA-B27 misfolding and ankylosing spondylitis. Mol Immunol. 2014;57(1):44–51. doi:10.1016/j.molimm.2013.07.013.

    Article  CAS  PubMed  Google Scholar 

  19. • Guiliano DB, North H, Panayoitou E, et al. Polymorphisms in the F pocket of HLA-B*27 subtypes strongly impact on assembly, chaperone interactions and heavy chain misfolding. Arthritis Rheumatol. 2016. doi:10.1002/art.39948. This paper enhances our understanding of the pathogenic role of HLA-B27.

    Google Scholar 

  20. Liu X, Hu LH, Li YR, Chen FH, Ning Y, Yao QF. The association of HLA-B*27 subtypes with ankylosing spondylitis in Wuhan population of China. Rheumatol Int. 2010;30(5):587–90.

    Article  CAS  PubMed  Google Scholar 

  21. Liu Y, Jiang L, Cai Q, Danoy P, Barnardo MC, Brown MA, et al. Predominant association of HLA-B*2704 with ankylosing spondylitis in Chinese Han patients. Tissue Antigens. 2010;75(1):61–4.

    Article  CAS  PubMed  Google Scholar 

  22. Hou TY, Chen HC, Chen CH, Chang DM, Liu FC, Lai JH. Usefulness of human leucocyte antigen-B27 subtypes in predicting ankylosing spondylitis: Taiwan experience. Intern Med J. 2007;37(11):749–52.

    PubMed  Google Scholar 

  23. Zou HY, Yu WZ, Wang Z, He J, Jiao M. Human leukocyte antigen-B27 alleles in Xinjiang Uygur patients with ankylosing spondylitis. Genet Mol Res. 2015;14(2):5652–7.

    Article  CAS  PubMed  Google Scholar 

  24. Cauli A, Vacca A, Mameli A, Passiu G, Fiorillo MT, Sorrentino R, et al. A Sardinian patient with ankylosing spondylitis and HLA-B*2709 co-occurring with HLA-B*1403. Arthritis Rheum. 2007;56(8):2807–9.

    Article  PubMed  Google Scholar 

  25. Olivieri I, D’Angelo S, Scarano E, Santospirito V, Padula A. The HLA-B*2709 subtype in a woman with early ankylosing spondylitis. Arthritis Rheum. 2007;56(8):2804–7.

    Article  Google Scholar 

  26. Cauli A, Vacca A, Dessole G, Fiorillo MT, Porru G, Ibba V, et al. HLA-B*2709 and lack of susceptibility to sacroiliitis: further support from the clinic. Clin Exp Rheumatol. 2008;26(6):1111–2.

    CAS  PubMed  Google Scholar 

  27. Siala M, Mahfoudh N, Gdoura R, et al. Distribution of HLA-B27 and its alleles in patients with reactive arthritis and with ankylosing spondylitis in Tunisia. Rheumatol Int. 2009;29(10):1193–6.

    Article  CAS  PubMed  Google Scholar 

  28. Ben Radhia K, Ayed-Jendoubi S, Sfar I, et al. Distribution of HLA-B*27 subtypes in Tunisians and their association with ankylosing spondylitis. Joint Bone Spine. 2008;75(2):172–5.

    Article  PubMed  Google Scholar 

  29. Birinci A, Bilgici A, Kuru O, Durupinar B. HLA-B27 polymorphism in Turkish patients with ankylosing spondylitis. Rheumatol Int. 2006;26(4):285–7.

    Article  CAS  PubMed  Google Scholar 

  30. Zhou HY, Yu WZ, Wang Z, et al. Human leukocyte antigen-B27 alleles in Xinjiang Uygur patients with ankylosing spondylitis. Genet Mol Res. 2015;14(2):5652–7.

    Article  Google Scholar 

  31. Shankarkumar U, Ghosh K, Mohanty D. HLA B27 polymorphism in Western India. B*2714 was observed in a patient with ankylosing spondylitis. Tissue Antigens. 2002;60(1):98–101.

    Article  CAS  PubMed  Google Scholar 

  32. García-Fernández S, Gonzalez S, Miña Blanco A, et al. New insights regarding HLA-B27 diversity in the Asian population. Tissue Antigens. 2001;58(4):259–62.

    Article  PubMed  Google Scholar 

  33. Diyarbakir E, Eyerci N, Melikoglu M, Topcu A, Pirim I. HLA B27 subtype distribution among patients with ankylosing spondylitis in eastern Turkey. Genet Test Mol Biomarkers. 2012;16(5):456–8.

    Article  CAS  PubMed  Google Scholar 

  34. Mou Y, Wu Z, Gu J, Liao Z, Lin Z, Wei Q, et al. HLA-B27 polymorphism in patients with juvenile and adult-onset ankylosing spondylitis in Southern China. Tissue Antigens. 2010;75(1):56–60.

    Article  CAS  PubMed  Google Scholar 

  35. Stanevicha V, Eglite J, Zavadska D. HLA B27 allele types in homogeneous groups of juvenile idiopathic arthritis patients in Latvia. Pediatr Rheumatol Online J. 2010;8:26. doi:10.1186/1546-0096-8-26.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ma HJ, Hu FP. Diversity of human leukocyte antigen-B27 alleles in Han population of Hunan province, southern China. Tissue Antigens. 2006;68(2):163–6.

    Article  CAS  PubMed  Google Scholar 

  37. Grubić Z, Kerhin-Brkljacić V, Perić P, Cecuk E, Kastelan A. Variation in HLA-B27 gene subtypes and susceptibility of ankylosing spondylitis in the Croatian population. Reumatizam. 2001;48(1):7–11.

    PubMed  Google Scholar 

  38. Chavan H, Samant R, Deshpande A, Mankeshwar R. Correlation of HLA B27 subtypes with clinical features of ankylosing spondylitis. Int J Rheum Dis. 2011;14(4):369–74. doi:10.1111/j.1756-185X.2011.01635.x.

    Article  PubMed  Google Scholar 

  39. Qi J, Li Q, Lin Z, Liao Z, Wei Q, et al. Higher risk of uveitis and dactylitis and older age of onset among ankylosing spondylitis patients with HLA-B*2705 than patients with HLA-B*2704 in the Chinese population. Tissue Antigens. 2013;82(6):380–6. doi:10.1111/tan.12254.

    Article  CAS  PubMed  Google Scholar 

  40. Li H, Li Q, Ji C, Gu J. Ankylosing spondylitis patients with HLA-B*2704 have more uveitis than patients with HLA-B*2705 in a North Chinese population. Ocul Immunol Inflamm. 2016;18:1–5.

    Google Scholar 

  41. Wu Z, Lin Z, Wei Q, Gu J. Clinical features of ankylosing spondylitis may correlate with HLA-B27 polymorphism. Rheumatol Int. 2009;29(4):389–92.

    Article  PubMed  Google Scholar 

  42. Mou Y, Zhang P, Li Q, et al. Clinical features in juvenile-onset ankylosing spondylitis patients carrying different B27 subtypes. Biomed Res Int. 2015;2015:594878. doi:10.1155/2015/594878.].

    Article  PubMed  PubMed Central  Google Scholar 

  43. Khan MA, Kushner I, Braun WE, Zachary AA, Steinberg AG. HLA– B27 homozygosity in ankylosing spondylitis: relationship to risk and severity. Tissue Antigens. 1978;11:434–8.

    Article  CAS  PubMed  Google Scholar 

  44. 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(6):775–80.

    Article  CAS  PubMed  Google Scholar 

  45. Kim TJ, Na KS, Lee HJ, Lee B, Kim TH. HLA-B27 Homozygosity has no influence on clinical manifestations and functional disability in Ankylosing Spondylitis. Clin Exp Rheumatol. 2009;27(4):574–9.

    PubMed  Google Scholar 

  46. Kim TJ, Sung IH, Lee S, et al. HLA-B27 homozygosity has no influence on radiographic damage in ankylosing spondylitis: observation study of Korean Spondyloarthropathy Registry (OSKAR) data. Joint Bone Spine. 2013;80(5):488–91.

    Article  CAS  PubMed  Google Scholar 

  47. Goulder PJ, Watkins DI. Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol. 2008;8:619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McKiernan SM, Hagan R, Curry M, McDonald GS, Kelly A, Nolan N, et al. Distinct MHC class I and II alleles are associated with hepatitis C viral clearance, originating from a single source. Hepatology. 2004;40:108–14.

  49. •• Neumann-Haefelin C. HLA-B27-mediated protection in HIV and hepatitis C virus infection and pathogenesis in spondyloarthritis: two sides of the same coin? Curr Opin Rheumatol. 2013;25(4):426–33. The author reviews the multiple virological and immunological mechanisms that have been suggested to contribute to HLA-B27-mediated protection in HIV and HCV infection. It is suggested that some of these mechanisms may also be involved in HLA-B27-associated pathogenesis in AS and associated forms of spondyloarthritis.

    Article  CAS  PubMed  Google Scholar 

  50. Neumann-Haefelin C, Oniangue-Ndza C, Kuntzen T, et al. HLA-B27 selects for rare escape mutations that significantly impair Hepatitis C virus replication and require compensatory mutations. Hepatology. 2011;54(4):1157–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. • Hecht L, Dormer A. The evolutionary significance of certain amino acid substitutions and their consequences for HIV-1 immunogenicity toward HLA’s A*0201 and B*27. Bioinformation. 2013;9(6):315–20. This study shows that the vaccines based upon the envelope glycoprotein of HIV are unlikely to be effective in eliciting an immune response in vivo in HLA-B*27+ individuals because the predominant 9-mers IRIGPGQAF of gp120 are significantly less immunogenic toward HLA-B*27 than to HLA-A*02.

    Article  PubMed  PubMed Central  Google Scholar 

  52. •• Nitschke K, Barriga A, Schmidt J, et al. HLA-B*27 subtype specificity determines targeting and viral evolution of a hepatitis C virus-specific CD8+ T cell epitope. J Hepatol. 2014;60(1):22–9. This important study shows that a hepatitis C virus-specific CD8+ T cell epitope NS5B2820 is immunodominant in the context of HLA-B*27:02 (that is frequent in the Mediterranean populations), but is not restricted by HLA-B*27:05 (the most common subtype worldwide). These findings may have important implications for the selection of epitopes for global vaccines.

    Article  CAS  PubMed  Google Scholar 

  53. Johnsen SS, Bakland G, Nossent JC. The distribution of HLA-B27 subtype in patients with ankylosing spondylitis in Northern Norway. Scand J Rheumatol. 2014;43(4):296–300.

    Article  CAS  PubMed  Google Scholar 

  54. Baech J, Schmidt-Olsen S, Steffensen R, et al. Frequency of HLA-B27 subtypes in a Danish patient population and in Danish patients with ankylosing spondylitis. Tissue Antigens. 1997;49(5):499–502.

    Article  CAS  PubMed  Google Scholar 

  55. Mathieu A, Paladini F, Vacca A, et al. The interplay between the geographic distribution of HLA-B27 alleles and their role in infectious and autoimmune diseases: a unifying hypothesis. Autoimmun Rev. 2009;8(5):420–5.

    Article  CAS  PubMed  Google Scholar 

  56. Rana MK, Luthra-Guptasarma M. Differences in conformational stability of the two alpha domains of the disease associated and non-disease-associated subtypes of HLA-B27. Int J Biol Macromol. 2017;95(Part A):233-45. doi:10.1016/j.ijbiomac.2016.08.066.

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  1. Case Western Reserve University, Cleveland, OH, USA

    Muhammad A. Khan

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Correspondence to Muhammad A. Khan.

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This article is part of the Topical Collection on Spondyloarthritis

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Khan, M.A. An Update on the Genetic Polymorphism of HLA-B*27 With 213 Alleles Encompassing 160 Subtypes (and Still Counting). Curr Rheumatol Rep 19, 9 (2017). https://doi.org/10.1007/s11926-017-0640-1

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