Skip to main content
SpringerLink
Log in

Genetics of Behçet’s Disease

  • Chapter
  • First Online:
Behçet Syndrome

Abstract

Behçet’s disease (BD) is a multifactorial disease with a strong genetic background. Higher frequencies of patients with a positive family history for BD were reported from the Middle East and among patients who are HLA-B∗51 positive or with juvenile disease onset. Sibling recurrence risk ratio (λs) was estimated as 11.4–52.5 in high prevalence regions. BD is strongly associated with a class I major histocompatibility complex (MHC) allele, HLA-B∗51, and this association was confirmed in various ethnic groups. Distribution of HLA-B∗51 allele in healthy population is suggested to play a role in the disease clustering in an area extending from the Mediterranean basin to Japan. The HLA-B∗51-driven pathogenic mechanisms are still unknown, but weaker associations with other HLA-B (i.e., HLA-B∗49 as protective and HLA-B∗15, HLA-B∗27, and HLA-B∗57 as risk) and HLA-A (i.e., HLA-A∗03 as protective and HLA-A∗26 as risk) alleles, which are polymorphic at antigen-binding sites, suggest the importance of peptide binding in the pathogenesis. Identification of an epistatic interaction between certain ERAP1 haplotypes and HLA-B∗51 supported further the important role of the endoplasmic reticulum peptidome. Accumulation of low-affinity peptides for loading on the antigen-binding groove of HLA-B∗51 may affect their potential to fold properly and to present the peptides to CD8+ cells. Genome-wide association studies in different ethnic groups revealed several non-HLA polymorphisms increasing the susceptibility to BD. Most of these associations have immunoregulatory functions, and they are considered to be affecting the sensitivity to different environmental triggers as well as responsible for the pathergic activation of innate and adaptive immune responses as well as endothelial cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Gül A. Behçet’s disease: an update on the pathogenesis. Clin Exp Rheumatol. 2001;19(Suppl 24):S6–12.

    PubMed  Google Scholar 

  2. Zierhut M, Mizuki N, Ohno S, et al. Immunology and functional genomics of Behçet’s disease. Cell Mol Life Sci. 2003;60:1903–22.

    Article  CAS  PubMed  Google Scholar 

  3. Gül A. Pathogenesis of Behçet’s disease: autoinflammatory features and beyond. Semin Immunopathol. 2015;37:413–8.

    Article  PubMed  Google Scholar 

  4. Fowler TJ, Humpston DJ, Nussey AM, Small M. Behcet’s syndrome with neurological manifestations in two sisters. Br Med J. 1968;2:473–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mason RM, Barnes CG. Behçet’s syndrome with arthritis. Ann Rheum Dis. 1969;28:95–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Fadli ME, Youssef MM. Neuro-Behçet’s syndrome in the United Arab Republic. Eur Neurol. 1973;9:76–89.

    Article  CAS  PubMed  Google Scholar 

  7. Chajek T, Fainaru M. Behçet’s disease: Report of 41 cases and a review of the literature. Medicine (Baltimore). 1975;54:179–96.

    Article  CAS  Google Scholar 

  8. Goolamali SK, Comaish JS, Hassanyeh F. Familial Behçet’s syndrome. Br J Dermatol. 1976;95:637–42.

    Article  CAS  PubMed  Google Scholar 

  9. Nahir M, Scharf Y, Gidoni O, et al. HL-A antigens in Behçet’s disease. A family study. Dermatologica. 1978;156:205–8.

    Article  CAS  PubMed  Google Scholar 

  10. Abdel-Aziz AH, Fairburn EA. Familial Behcet’s syndrome. Cutis. 1978;21:649–52.

    CAS  PubMed  Google Scholar 

  11. Dündar SV, Gençalp U, Simşek H. Familial cases of Behcet’s disease. Br J Dermatol. 1985;113:319–21.

    Article  PubMed  Google Scholar 

  12. Chajek-Shaul T, Pisanty S, Knobler H, et al. HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Behçet’s syndrome. Am J Med. 1987;83:666–72.

    Article  CAS  PubMed  Google Scholar 

  13. Akpolat T, Koç Y, Yeniay I, et al. Familial Behçet’s disease. Eur J Med. 1992;1:391–5.

    CAS  PubMed  Google Scholar 

  14. Villanueva JL, Gonzalez-Dominguez J, Gonzalez-Fernandez R, et al. HLA antigen familial study in complete Behçet’s syndrome affecting three sisters. Ann Rheum Dis. 1993;52:155–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nishiura K, Kotake S, Ichiishi A, Matsuda H. Familial occurrence of Behçet’s disease. Jpn J Ophthalmol. 1996;40:255–9.

    CAS  PubMed  Google Scholar 

  16. Nishiyama M, Nakae K, Umehara T. A study of familial occurrence of Behçet’s disease with and without ocular lesions. Jpn J Ophthalmol. 2001;45:313–6.

    Article  CAS  PubMed  Google Scholar 

  17. Fietta P. Behçet’s disease: familial clustering and immunogenetics. Clin Exp Rheumatol. 2005;23(Suppl 38):S96–105.

    CAS  PubMed  Google Scholar 

  18. Gül A, Inanç M, Ocal L, et al. Familial aggregation of Behçet’s disease in Turkey. Ann Rheum Dis. 2000;59:622–5.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Treudler R, Orfanos CE, Zouboulis CC. Twenty-eight cases of juvenile-onset Adamantiades-Behçet disease in Germany. Dermatology. 1999;199:15–9.

    Article  CAS  PubMed  Google Scholar 

  20. Koné-Paut I, Geisler I, Wechsler B, et al. Familial aggregation in Behçet’s disease: high frequency in siblings and parents of pediatric probands. J Pediatr. 1999;135:89–93.

    Article  PubMed  Google Scholar 

  21. Hayasaka S, Kurome H, Noda S. HLA antigens in a Japanese family with Behçet’s disease. Graefes Arch Clin Exp Ophthalmol. 1994;232:589–90.

    Article  CAS  PubMed  Google Scholar 

  22. Nishiyama M, Nakae K, Kuriyama T, et al. A study among related pairs of Japanese patients with familial Behçet’s disease: group comparisons by interval of disease onsets. J Rheumatol. 2002;29:743–7.

    PubMed  Google Scholar 

  23. Aronsson A, Tegner E. Behçet’s syndrome in two brothers. Acta Derm Venereol. 1983;63:73–4.

    CAS  PubMed  Google Scholar 

  24. Fresko I, Soy M, Hamuryudan V, et al. Genetic anticipation in Behçet’s syndrome. Ann Rheum Dis. 1998;57:45–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hamuryudan V, Yurdakul S, Ozbakir F, et al. Monozygotic twins concordant for Behçet’s syndrome. Arthritis Rheum. 1991;34:1071–2.

    Article  CAS  PubMed  Google Scholar 

  26. Gül A, Inanç M, Ocal L, et al. HLA-B51 negative monozygotic twins discordant for Behçet’s disease. Br J Rheumatol. 1997;36:922–3.

    Article  PubMed  Google Scholar 

  27. Kobayashi T, Sudo Y, Okamura S, et al. Monozygotic twins concordant for intestinal Behçet’s disease. J Gastroenterol. 2005;40:421–5.

    Article  PubMed  Google Scholar 

  28. Masatlioglu S, Seyahi E, Tahir Turanli E, et al. A twin study in Behçet’s syndrome. Clin Exp Rheumatol. 2010;28(4 Suppl 60):S62–6.

    PubMed  Google Scholar 

  29. Verity DH, Marr JE, Ohno S, et al. Behçet’s disease, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens. 1999;54:213–20.

    Article  CAS  PubMed  Google Scholar 

  30. Ohno S, Ohguchi M, Hirose S, et al. Close association of HLA-Bw51 with Behçet’s disease. Arch Ophthalmol. 1982;100:1455–8.

    Article  CAS  PubMed  Google Scholar 

  31. Abi-Rached L, Jobin MJ, Kulkarni S, et al. The shaping of modern human immune systems by multiregional admixture with archaic humans. Science. 2011;334:89–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ohno S, Aoki K, Sugiura S, et al. HL-A5 and Behçet’s disease. Lancet. 1973;2:1383–4.

    Article  CAS  PubMed  Google Scholar 

  33. Ohno S, Nakayama E, Sugiura S, et al. Specific histocompatibility antigens associated with Behçet’s disease. Am J Ophthalmol. 1975;80:636–41.

    Article  Google Scholar 

  34. Kilmartin DJ, Finch A, Acheson RW. Primary association of HLA-B51 with Behçet’s disease in Ireland. Br J Ophthalmol. 1997;81:649–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ambresin A, Tran T, Spertini F, Herbort C. Behçet’s disease in Western Switzerland: epidemiology and analysis of ocular involvement. Ocul Immunol Inflamm. 2002;10:53–63.

    Article  CAS  PubMed  Google Scholar 

  36. Pipitone N, Boiardi L, Olivieri I, et al. Clinical manifestations of Behçet’s disease in 137 Italian patients: results of a multicenter study. Clin Exp Rheumatol. 2004;22(Suppl 36):S46–51.

    CAS  PubMed  Google Scholar 

  37. Bettencourt A, Pereira C, Carvalho L, et al. New insights of HLA class I association to Behçet’s disease in Portuguese patients. Tissue Antigens. 2008;72:379–82.

    Article  CAS  PubMed  Google Scholar 

  38. Gül A, Hajeer AH, Worthington J, et al. Evidence for linkage of the HLA-B locus in Behçet’ disease, obtained using the transmission disequilibrium test. Arthritis Rheum. 2001;44:239–40.

    Article  PubMed  Google Scholar 

  39. de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLA-B51/B5 and the risk of Behçet’ disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum. 2009;61:1287–96.

    Article  PubMed  CAS  Google Scholar 

  40. Remmers EF, Cosan F, Kirino Y, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease. Nat Genet. 2010;42:698–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Mizuki N, Meguro A, Ota M, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet. 2010;42:703–6.

    Article  CAS  PubMed  Google Scholar 

  42. Kirino Y, Bertsias G, Ishigatsubo Y, et al. Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B∗51 and ERAP1. Nat Genet. 2013;45:202–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee YJ, Horie Y, Wallace GR, et al. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet’s disease. Ann Rheum Dis. 2013;72:1510–6.

    Article  CAS  PubMed  Google Scholar 

  44. Kappen JH, Medina-Gomez C, van Hagen PM, et al. Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behçet disease. PLoS One. 2015;10:e0119085.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Hughes T, Coit P, Adler A, et al. Identification of multiple independent susceptibility loci in the HLA region in Behçet’s disease. Nat Genet. 2013;45:319–24.

    Article  CAS  PubMed  Google Scholar 

  46. Ombrello MJ, Kirino Y, de Bakker PI, Gül A, Kastner DL, Remmers EF. Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 2014;111:8867–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Takeuchi M, Mizuki N, Meguro A, et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility. Nat Genet. 2017;49:438–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sano K, Yabuki K, Imagawa Y, et al. The absence of disease-specific polymorphisms within the HLA-B51 gene that is the susceptible locus for Behçet’s disease. Tissue Antigens. 2001;58:77–82.

    Article  CAS  PubMed  Google Scholar 

  49. Takemoto Y, Naruse T, Namba K, et al. Re-evaluation of heterogeneity in HLA-B∗510101 associated with Behçet’s disease. Tissue Antigens. 2008;72:347–53.

    Article  CAS  PubMed  Google Scholar 

  50. Arber N, Klein T, Meiner Z, et al. Close association of HLA-B51 and B52 in Israeli patients with Behçet’s syndrome. Ann Rheum Dis. 1991;50:351–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sugisaki K, Saito R, Takagi T, et al. HLA-B52-positive vasculo-Behçet disease: usefulness of magnetic resonance angiography, ultrasound study, and computed tomographic angiography for the early evaluation of multiarterial lesions. Mod Rheumatol. 2005;15:56–61.

    Article  PubMed  Google Scholar 

  52. Falk K, Rötzschke O, Takiguchi M, et al. Peptide motifs of HLA-B51, -B52 and -B78 molecules, and implications for Behçet’s disease. Int Immunol. 1995;7:223–8.

    Article  CAS  PubMed  Google Scholar 

  53. Sakaguchi T, Ibe M, Miwa K, et al. Predominant role of N-terminal residue of nonamer peptides in their binding to HLA-B∗ 5101 molecules. Immunogenetics. 1997;46:245–8.

    Article  CAS  PubMed  Google Scholar 

  54. Lemmel C, Rammensee H-G, Stevanovic S. Peptide motif of HLA-B∗5101 and the linkage to Behçet’s disease. In: Zierhut M, Ohno S, editors. Immunology of Behçet’s disease. Lisse: Swets & Zeitlinger; 2003. p. 127–37.

    Google Scholar 

  55. Mizuki N, Inoko H, Ando H, et al. Behçet’s disease associated with one of the HLA-B51 subantigens, HLA-B∗ 5101. Am J Ophthalmol. 1993;116:406–9.

    Article  CAS  PubMed  Google Scholar 

  56. Mizuki N, Ota M, Katsuyama Y, et al. Sequencing-based typing of HLA-B∗51 alleles and the significant association of HLA-B∗5101 and -B∗5108 with Behçet’s disease in Greek patients. Tissue Antigens. 2002;59:118–21.

    Article  CAS  PubMed  Google Scholar 

  57. Pirim I, Atasoy M, Ikbal M, et al. HLA class I and class II genotyping in patients with Behcet’s disease: a regional study of eastern part of Turkey. Tissue Antigens. 2004;64:293–7.

    Article  CAS  PubMed  Google Scholar 

  58. Kera J, Mizuki N, Ota M, et al. Significant associations of HLA-B∗5101 and B∗5108, and lack of association of class II alleles with Behçet’s disease in Italian patients. Tissue Antigens. 1999;54:565–71.

    Article  CAS  PubMed  Google Scholar 

  59. Yabuki K, Ohno S, Mizuki N, et al. HLA class I and II typing of the patients with Behçet’s disease in Saudi Arabia. Tissue Antigens. 1999;54:273–7.

    Article  CAS  PubMed  Google Scholar 

  60. Yasuoka H, Okazaki Y, Kawakami Y, et al. Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet’s disease. Arthritis Rheum. 2004;50:3658–62.

    Article  CAS  PubMed  Google Scholar 

  61. Martin MP, Gao X, Lee J-H, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet. 2002;31:429–34.

    Article  CAS  PubMed  Google Scholar 

  62. Gül A, Uyar FA, Inanç M, et al. A weak association of HLA-B∗2702 with Behçet’s disease. Genes Immun. 2002;3:368–72.

    Article  PubMed  CAS  Google Scholar 

  63. Erer B, Takeuchi M, Ustek D, et al. Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet’s disease. Genes Immun. 2016;17:396–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hill A, Takiguchi M, McMichael A. Different rates of HLA class I molecule assembly which are determined by amino acid sequence in the alpha 2 domain. Immunogenetics. 1993;37:95–101.

    Article  CAS  PubMed  Google Scholar 

  65. Turner MJ, Sowders DP, DeLay ML, et al. HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol. 2005;175:2438–48.

    Article  CAS  PubMed  Google Scholar 

  66. Takeuchi M, Ombrello MJ, Kirino Y, et al. A single endoplasmic reticulum aminopeptidase-1 protein allotype is a strong risk factor for Behçet’s disease in HLA-B∗51 carriers. Ann Rheum Dis. 2016;75:2208–11.

    Article  CAS  PubMed  Google Scholar 

  67. Guasp P, Alvarez-Navarro C, Gomez-Molina P, et al. The peptidome of Behçet’s disease-associated HLA-B∗51:01 includes two subpeptidomes differentially shaped by endoplasmic reticulum aminopeptidase 1. Arthritis Rheumatol. 2016;68:505–15.

    Article  CAS  PubMed  Google Scholar 

  68. Guasp P, Barnea E, González-Escribano MF, et al. The Behçet’s disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B∗51 peptidome by differential subpeptidome processing. J Biol Chem. 2017;292:9680–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. McGonagle D, Aydin SZ, Gül A, Mahr A, Direskeneli H. ‘MHC-I-opathy’-unified concept for spondyloarthritis and Behçet disease. Nat Rev Rheumatol. 2015;11:731–40.

    Article  CAS  PubMed  Google Scholar 

  70. Wildner G, Thurau SR. Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease. Eur J Immunol. 1994;24:2579–85.

    Article  CAS  PubMed  Google Scholar 

  71. Kurhan-Yavuz S, Direskeneli H, Bozkurt N, et al. Anti-MHC autoimmunity in Behçet’s disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis. Clin Exp Immunol. 2000;120:162–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Takeno M, Kariyone A, Yamashita N, et al. Excessive function of peripheral blood neutrophils from patients with Behçet’s disease and from HLA-B51 transgenic mice. Arthritis Rheum. 1995;38:426–33.

    Article  CAS  PubMed  Google Scholar 

  73. Sensi A, Gavioli R, Spisani S, et al. HLA B51 antigen associated with neutrophil hyper-reactivity. Dis Markers. 1991;9:327–31.

    CAS  PubMed  Google Scholar 

  74. Taurog JD, Maika SD, Satumtira N, et al. Inflammatory disease in HLA-B27 transgenic rats. Immunol Rev. 1999;169:209–23.

    Article  CAS  PubMed  Google Scholar 

  75. Miretti MM, Walsh EC, Ke X, et al. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet. 2005;76:634–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mizuki N, Ota M, Kimura M, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease. Proc Natl Acad Sci U S A. 1997;94:1298–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hughes EH, Collins RW, Kondeatis E, et al. Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Behcet’s disease in Caucasian patients. Tissue Antigens. 2005;66:195–9.

    Article  CAS  PubMed  Google Scholar 

  78. Mizuki N, Meguro A, Tohnai I, et al. Association of major histocompatibility complex class I chain-related gene A and HLA-B alleles with Behçet’s disease in Turkey. Jpn J Ophthalmol. 2007;51:431–6.

    Article  PubMed  Google Scholar 

  79. Mizuki N, Ota M, Yabuki K, et al. Localization of the pathogenic gene of Behçet’s disease by microsatellite analysis of three different populations. Invest Ophthalmol Vis Sci. 2000;41:3702–8.

    CAS  PubMed  Google Scholar 

  80. Mizuki N, Ohno S, Tanaka H, et al. Association of HLA-B51 and lack of association of class II alleles with Behçet’s disease. Tissue Antigens. 1992;40:22–30.

    Article  CAS  PubMed  Google Scholar 

  81. Gül A, Hajeer AH, Worthington J, et al. Linkage mapping of a novel susceptibility locus for Behçet’s disease to chromosome 6p22-23. Arthritis Rheum. 2001;44:2693–6.

    Article  PubMed  Google Scholar 

  82. Mizuki N, Ohno S, Ando H, et al. HLA-C genotyping of patient with Behçet’s disease in the Japanese population. Hum Immunol. 1996;50:47–53.

    Article  CAS  PubMed  Google Scholar 

  83. Sanz L, González-Escribano F, de Pablo R, et al. HLA-Cw∗1602: a new susceptibility marker of Behçet’s disease in southern Spain. Tissue Antigens. 1998;51:111–4.

    Article  CAS  PubMed  Google Scholar 

  84. Park KS, Park JS, Nam JH, et al. HLA-E∗0101 and HLA-G∗010101 reduce the risk of Behcet’s disease. Tissue Antigens. 2007;69:139–44.

    Article  CAS  PubMed  Google Scholar 

  85. Meguro A, Inoko H, Ota M, et al. Genetics of Behcet’s disease inside and outside the MHC. Ann Rheum Dis. 2010;69:747–54.

    Article  CAS  PubMed  Google Scholar 

  86. Gül A, Ohno S. Genetics of Behçet’s disease. In: Yazici Y, Yazici H, editors. Behçet syndrome. New York: Springer; 2010. p. 265–75.

    Chapter  Google Scholar 

  87. Karasneh J, Gül A, Ollier WE, et al. Whole-genome screening for susceptibility genes in multicase families with Behçet’s disease. Arthritis Rheum. 2005;52:1836–42.

    Article  CAS  PubMed  Google Scholar 

  88. Gül A. Genetics of Behçet’s disease: lessons learned from genomewide association studies. Curr Opin Rheumatol. 2014;26:56–63.

    Article  PubMed  CAS  Google Scholar 

  89. Fei Y, Webb R, Cobb BL, Direskeneli H, Saruhan-Direskeneli G, Sawalha AH. Identification of novel genetic susceptibility loci for Behçet’s disease using a genome-wide association study. Arthritis Res Ther. 2009;11:R66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Hou S, Yang Z, Du L, et al. Identification of a susceptibility locus in STAT4 for Behcet’s disease in Han Chinese in a genome-wide association study. Arthritis Rheum. 2012;64:4104–13.

    Article  CAS  PubMed  Google Scholar 

  91. Ortiz-Fernández L, Carmona FD, Montes-Cano MA, et al. Genetic analysis with the Immunochip platform in Behçet disease. Identification of residues associated in the HLA Class I region and new susceptibility loci. PLoS One. 2016;11:e0161305.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Deng Y, Zhu W, Zhou X. Immune regulatory genes are major genetic factors to Behcet disease: Systematic Review. Open Rheumatol J. 2018;12:70–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Jiang Z, Hennein L, Tao Y, Tao L. Interleukin-23 receptor gene polymorphism may enhance expression of the IL-23 Receptor, IL-17, TNF-α and IL-6 in Behcet’s disease. PLoS One. 2015;10:e0134632.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Sonmez C, Yucel AA, Yesil TH, et al. Correlation between IL-17A/F, IL-23, IL-35 and IL-12/-23 (p40) levels in peripheral blood lymphocyte cultures and disease activity in Behcet’s patients. Clin Rheumatol. 2018;37:2797–804.

    Article  PubMed  Google Scholar 

  95. Alipour S, Nouri M, Khabbazi A, et al. Hypermethylation of IL-10 gene is responsible for its low mRNA expression in Behçet’s disease. J Cell Biochem. 2018;119:6614–22.

    Article  CAS  PubMed  Google Scholar 

  96. Nakano H, Kirino Y, Takeno M, et al. GWAS-identified CCR1 and IL10 loci contribute to M1 macrophage-predominant inflammation in Behçet’s disease. Arthritis Res Ther. 2018;20:124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Xavier JM, Shahram F, Sousa I, et al. FUT2: filling the gap between genes and environment in Behçet’s disease? Ann Rheum Dis. 2015;74:618–24.

    Article  CAS  PubMed  Google Scholar 

  98. Pickard JM, Maurice CF, Kinnebrew MA, et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature. 2014;514:638–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Consolandi C, Turroni S, Emmi G, et al. Behçet’s syndrome patients exhibit specific microbiome signature. Autoimmun Rev. 2015;14:269–76.

    Article  PubMed  Google Scholar 

  100. Ye Z, Zhang N, Wu C, Zhang X, Wang Q, Huang X, et al. A metagenomic study of the gut microbiome in Behcet’s disease. Microbiome. 2018;6:135.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Shimizu J, Kubota T, Takada E, et al. Relative abundance of Megamonas hypermegale and Butyrivibrio species decreased in the intestine and its possible association with the T cell aberration by metabolite alteration in patients with Behcet’s disease. Clin Rheumatol. 2019;38(5):1437–45.

    Article  PubMed  Google Scholar 

  102. Gül A. Genome-wide association studies in Behçet’s disease: expectations and promises. Clin Exp Rheumatol. 2011;29(4 Suppl 67):S3–5.

    PubMed  Google Scholar 

  103. Kirino Y, Zhou Q, Ishigatsubo Y, et al. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. Proc Natl Acad Sci U S A. 2013;110:8134–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xavier JM, Shahram F, Davatchi F, et al. Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behçet’s disease. Arthritis Rheum. 2012;64:2761–72.

    Article  CAS  PubMed  Google Scholar 

  105. Carapito R, Shahram F, Michel S, et al. On the genetics of the Silk Route: association analysis of HLA, IL10, and IL23R-IL12RB2 regions with Behçet’s disease in an Iranian population. Immunogenetics. 2015;67:289–93.

    Article  CAS  PubMed  Google Scholar 

  106. Wu Z, Zheng W, Xu J, et al. IL10 polymorphisms associated with Behçet’s disease in Chinese Han. Hum Immunol. 2014;75:271–6.

    Article  CAS  PubMed  Google Scholar 

  107. Jiang Z, Yang P, Hou S, Du L, Xie L, Zhou H, Kijlstra A. IL-23R gene confers susceptibility to Behcet’s disease in a Chinese Han population. Ann Rheum Dis. 2010;69:1325–8.

    Article  CAS  PubMed  Google Scholar 

  108. Kang EH, Kim S, Park MY, et al. Behçet’s disease risk association fine-mapped on the IL23R-IL12RB2 intergenic region in Koreans. Arthritis Res Ther. 2017;19:227.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Hou S, Xiao X, Li F, Jiang Z, Kijlstra A, Yang P. Two-stage association study in Chinese Han identifies two independent associations in CCR1/CCR3 locus as candidate for Behçet’s disease susceptibility. Hum Genet. 2012;131:1841–50.

    Article  CAS  PubMed  Google Scholar 

  110. Sousa I, Shahram F, Francisco D, et al. Brief report: association of CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 with Behçet’s disease in Iranians. Arthritis Rheumatol. 2015;67:2742–8.

    Article  PubMed  Google Scholar 

  111. Jiang Y, Wang H, Yu H, Li L, Xu D, Hou S, et al. Two Genetic Variations in the IRF8 region are associated with Behçet’s disease in Han Chinese. Sci Rep. 2016;6:19651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Wu P, Du L, Hou S, Su G, et al. Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behcet’s disease in a Chinese Han population. Br J Ophthalmol. 2018;102:1308–14.

    Article  PubMed  Google Scholar 

  113. Burillo-Sanz S, Montes-Cano MA, García-Lozano JR, et al. Behçet’s disease and genetic interactions between HLA-B∗51 and variants in genes of autoinflammatory syndromes. Sci Rep. 2019;9:2777.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Sawalha AH, Hughes T, Nadig A, et al. A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet’s disease. Arthritis Rheum. 2011;63:3607–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Hou S, Shu Q, Jiang Z, Chen Y, Li F, Chen F, et al. Replication study confirms the association between UBAC2 and Behçet’s disease in two independent Chinese sets of patients and controls. Arthritis Res Ther. 2012;14:R70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Yamazoe K, Meguro A, Takeuchi M, Shibuya E, Ohno S, Mizuki N. Comprehensive analysis of the association between UBAC2 polymorphisms and Behçet’s disease in a Japanese population. Sci Rep. 2017;7:742.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Istanbul University, Istanbul Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Istanbul, Turkey

    Ahmet Gül

  2. Centre for Translational Inflammation Research, University of Birmingham Research Laboratories, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK

    Graham R. Wallace

Authors
  1. Ahmet Gül
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Graham R. Wallace
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmet Gül .

Editor information

Editors and Affiliations

  1. School of Medicine, New York University, New York, NY, USA

    Yusuf Yazici

  2. Department of Internal Medicine, Istanbul University, Istanbul, Turkey

    Gulen Hatemi

  3. Department of Rheumatology, Istanbul University, Istanbul, Turkey

    Emire Seyahi

  4. Department of Medicine, Academic Hospital, Istanbul, Turkey

    Hasan Yazici

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gül, A., Wallace, G.R. (2020). Genetics of Behçet’s Disease. In: Yazici, Y., Hatemi, G., Seyahi, E., Yazici, H. (eds) Behçet Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-030-24131-5_16

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-24131-5_16

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-24130-8

  • Online ISBN: 978-3-030-24131-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation