Advertisement

Genetics of Behçet’s Disease

  • Ahmet GülEmail author
  • Graham R. Wallace
Chapter

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-B51 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-B51, and this association was confirmed in various ethnic groups. Distribution of HLA-B51 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-B51-driven pathogenic mechanisms are still unknown, but weaker associations with other HLA-B (i.e., HLA-B49 as protective and HLA-B15, HLA-B27, and HLA-B57 as risk) and HLA-A (i.e., HLA-A03 as protective and HLA-A26 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-B51 supported further the important role of the endoplasmic reticulum peptidome. Accumulation of low-affinity peptides for loading on the antigen-binding groove of HLA-B51 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.

Keywords

Behçet’s disease Familial aggregation HLA-B51 ERAP1 Genome-wide association studies Immunochip studies IL-10 IL-23R FUT2 

References

  1. 1.
    Gül A. Behçet’s disease: an update on the pathogenesis. Clin Exp Rheumatol. 2001;19(Suppl 24):S6–12.PubMedGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Gül A. Pathogenesis of Behçet’s disease: autoinflammatory features and beyond. Semin Immunopathol. 2015;37:413–8.PubMedCrossRefGoogle Scholar
  4. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Mason RM, Barnes CG. Behçet’s syndrome with arthritis. Ann Rheum Dis. 1969;28:95–103.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Fadli ME, Youssef MM. Neuro-Behçet’s syndrome in the United Arab Republic. Eur Neurol. 1973;9:76–89.PubMedCrossRefGoogle Scholar
  7. 7.
    Chajek T, Fainaru M. Behçet’s disease: Report of 41 cases and a review of the literature. Medicine (Baltimore). 1975;54:179–96.CrossRefGoogle Scholar
  8. 8.
    Goolamali SK, Comaish JS, Hassanyeh F. Familial Behçet’s syndrome. Br J Dermatol. 1976;95:637–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Nahir M, Scharf Y, Gidoni O, et al. HL-A antigens in Behçet’s disease. A family study. Dermatologica. 1978;156:205–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Abdel-Aziz AH, Fairburn EA. Familial Behcet’s syndrome. Cutis. 1978;21:649–52.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Dündar SV, Gençalp U, Simşek H. Familial cases of Behcet’s disease. Br J Dermatol. 1985;113:319–21.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Akpolat T, Koç Y, Yeniay I, et al. Familial Behçet’s disease. Eur J Med. 1992;1:391–5.PubMedPubMedCentralGoogle Scholar
  14. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Nishiura K, Kotake S, Ichiishi A, Matsuda H. Familial occurrence of Behçet’s disease. Jpn J Ophthalmol. 1996;40:255–9.PubMedPubMedCentralGoogle Scholar
  16. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Fietta P. Behçet’s disease: familial clustering and immunogenetics. Clin Exp Rheumatol. 2005;23(Suppl 38):S96–105.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Gül A, Inanç M, Ocal L, et al. Familial aggregation of Behçet’s disease in Turkey. Ann Rheum Dis. 2000;59:622–5.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Treudler R, Orfanos CE, Zouboulis CC. Twenty-eight cases of juvenile-onset Adamantiades-Behçet disease in Germany. Dermatology. 1999;199:15–9.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 23.
    Aronsson A, Tegner E. Behçet’s syndrome in two brothers. Acta Derm Venereol. 1983;63:73–4.PubMedGoogle Scholar
  24. 24.
    Fresko I, Soy M, Hamuryudan V, et al. Genetic anticipation in Behçet’s syndrome. Ann Rheum Dis. 1998;57:45–8.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Hamuryudan V, Yurdakul S, Ozbakir F, et al. Monozygotic twins concordant for Behçet’s syndrome. Arthritis Rheum. 1991;34:1071–2.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 27.
    Kobayashi T, Sudo Y, Okamura S, et al. Monozygotic twins concordant for intestinal Behçet’s disease. J Gastroenterol. 2005;40:421–5.PubMedCrossRefGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 30.
    Ohno S, Ohguchi M, Hirose S, et al. Close association of HLA-Bw51 with Behçet’s disease. Arch Ophthalmol. 1982;100:1455–8.PubMedCrossRefGoogle Scholar
  31. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Ohno S, Aoki K, Sugiura S, et al. HL-A5 and Behçet’s disease. Lancet. 1973;2:1383–4.PubMedCrossRefGoogle Scholar
  33. 33.
    Ohno S, Nakayama E, Sugiura S, et al. Specific histocompatibility antigens associated with Behçet’s disease. Am J Ophthalmol. 1975;80:636–41.CrossRefGoogle Scholar
  34. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 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. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Erer B, Takeuchi M, Ustek D, et al. Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet’s disease. Genes Immun. 2016;17:396–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 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.PubMedCrossRefGoogle Scholar
  71. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 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.PubMedCrossRefGoogle Scholar
  73. 73.
    Sensi A, Gavioli R, Spisani S, et al. HLA B51 antigen associated with neutrophil hyper-reactivity. Dis Markers. 1991;9:327–31.PubMedGoogle Scholar
  74. 74.
    Taurog JD, Maika SD, Satumtira N, et al. Inflammatory disease in HLA-B27 transgenic rats. Immunol Rev. 1999;169:209–23.PubMedCrossRefGoogle Scholar
  75. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 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.PubMedCrossRefGoogle Scholar
  78. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 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.PubMedPubMedCentralGoogle Scholar
  80. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 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.PubMedCrossRefGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedCrossRefGoogle Scholar
  86. 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.CrossRefGoogle Scholar
  87. 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.PubMedCrossRefGoogle Scholar
  88. 88.
    Gül A. Genetics of Behçet’s disease: lessons learned from genomewide association studies. Curr Opin Rheumatol. 2014;26:56–63.PubMedCrossRefGoogle Scholar
  89. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 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.PubMedCrossRefGoogle Scholar
  91. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 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.PubMedCrossRefGoogle Scholar
  95. 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.PubMedCrossRefGoogle Scholar
  96. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 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.PubMedCrossRefGoogle Scholar
  98. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Consolandi C, Turroni S, Emmi G, et al. Behçet’s syndrome patients exhibit specific microbiome signature. Autoimmun Rev. 2015;14:269–76.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 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.PubMedCrossRefGoogle Scholar
  102. 102.
    Gül A. Genome-wide association studies in Behçet’s disease: expectations and promises. Clin Exp Rheumatol. 2011;29(4 Suppl 67):S3–5.PubMedGoogle Scholar
  103. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 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.PubMedCrossRefGoogle Scholar
  106. 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.PubMedCrossRefGoogle Scholar
  107. 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.PubMedCrossRefGoogle Scholar
  108. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 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.PubMedCrossRefGoogle Scholar
  110. 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.PubMedCrossRefGoogle Scholar
  111. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 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.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Istanbul University, Istanbul Faculty of Medicine, Department of Internal Medicine, Division of RheumatologyIstanbulTurkey
  2. 2.Centre for Translational Inflammation Research, University of Birmingham Research LaboratoriesUniversity of Birmingham, Queen Elizabeth HospitalBirminghamUK

Personalised recommendations