Skip to main content
SpringerLink
Log in

Behçet’s Syndrome According to Classical and Population Genetics

  • Chapter
  • First Online:
Behçet's Syndrome

Part of the book series: Rare Diseases of the Immune System ((RDIS))

  • 1352 Accesses

Abstract

Although the etiology of Behçet’s disease (BD) remains uncertain, genetic and environmental factors likely both play an important role in BD development. BD is strongly associated with the human leukocyte antigen (HLA) class I allele, HLA-B*51, in many different ethnic groups. However, the presence of HLA-B*51-negative BD patients suggests that other genetic and/or environmental factors are also important in the development of BD. Several genetic variations have been recently identified as susceptibility factors for the development of BD, especially with the help of genome-wide association studies. Those findings provide new insights into the etiology and pathophysiology of BD allowing for a clearer interpretation the molecular level, and translation of those genetic findings may lead to development of more accurate diagnostic tools and more effective treatment approaches for BD.

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 59.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 79.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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. Ohno S, Aoki K, Sugiura S et al (1973) Letter: HL-A5 and Behçet’s disease. Lancet 2:1383–1384

    Article  Google Scholar 

  2. Ohno S, Ohguchi M, Hirose S et al (1982) Close association of HLA-Bw51 with Behçets disease. Arch Ophthalmol 100:1455–1458

    Google Scholar 

  3. de Menthon M, Lavalley MP, Maldini C et al (2009) HLA-B51/B5 and the risk of Behçet’s disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum 61:1287–1296

    Article  PubMed  Google Scholar 

  4. Gul A, Ohno S (2012) HLA-B*51 and Behçet Disease. Ocul Immunol Inflamm 20:37–43

    Article  CAS  PubMed  Google Scholar 

  5. Mizuki N, Inoko H, Mizuki N et al (1992) Human leukocyte antigen serologic and DNA typing of Behçet’s disease and its primary association with B51. Invest Ophthalmol Vis Sci 33:3332–3340

    CAS  PubMed  Google Scholar 

  6. Verity DH, Marr JE, Ohno S et al (1999) Behçet’s disease, the silk road and HLA-B51: historical and geographical perspectives. Tissue Antigens 54:213–220

    Article  CAS  PubMed  Google Scholar 

  7. Al-Otaibi LM, Porter SR, Poate TWJ (2005) Behçet’s disease: a review. J Dent Res 84:209–222

    Article  CAS  PubMed  Google Scholar 

  8. Azizlerli G, Köse AA, Sarica R et al (2003) Prevalence of Behçet’s disease in Istanbul, Turkey. Int J Dermatol 42:803–806

    Article  PubMed  Google Scholar 

  9. Hirohata T, Kuratsune M, Nomura A et al (1975) Prevalence of Behçet’s syndrome in Hawaii, with particular references to the comparison of the Japanese in Hawaii and Japan. Hawaii Med J 34:244–246

    CAS  PubMed  Google Scholar 

  10. Ohno S, Char DH, Kimura SJ et al (1979) Clinical observations in Behçet’s disease. Jpn J Ophthalmol 23:126–131

    Google Scholar 

  11. Hughes T, Coit P, Adler A et al (2013) Identification of multiple independent susceptibility loci in the HLA region in Behçet’s disease identification of multiple independent susceptibility loci in the HLA region in Behçet’s disease. Nat Genet 45:319–324

    Article  CAS  PubMed  Google Scholar 

  12. Springer TA (1995) Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu Rev Physiol 57:827–872

    Article  CAS  PubMed  Google Scholar 

  13. Aydintug AO, Tokgoz G, Ozoran K et al (1995) Elevated levels of soluble intercellular adhesion molecule-1 correlate with disease activity in Behçet’s disease. Rheumatol Int 15:75–78

    Article  CAS  PubMed  Google Scholar 

  14. Verity DH, Wallace GR, Seed PT et al (1998) Soluble adhesion molecules in Behçet’s disease. Ocul Immunol Inflamm 6:81–92

    Article  CAS  PubMed  Google Scholar 

  15. Verity DH, Vaughan RW, Kondeatis E et al (2000) Intercellular adhesion molecule-1 gene polymorphisms in Behçet’s disease. Eur J Immunogenet 27:73–76

    Article  CAS  PubMed  Google Scholar 

  16. Kim EH, Mok JW, Bang DS et al (2003) Intercellular adhesion molecule-1 polymorphisms in Korean patients with Behçet’s disease. Korean Med Sci 18:415–418

    Article  CAS  Google Scholar 

  17. Chmaisse HN, Fakhoury HA, Salti NN et al (2006) The ICAM-1 469 T/C gene polymorphism but not 241 G/A is associated with Behçets disease in the Lebanese population. Saudi Med J 27:604–607

    PubMed  Google Scholar 

  18. Boiardi L, Salvarani C, Casali B et al (2001) Intercellular adhesion molecule-1 gene polymorphisms in Behçet’s Disease. J Rheumatol 28:1283–1287

    CAS  PubMed  Google Scholar 

  19. Ben Dhifallah I, Karray EF, Sassi F et al (2010) Intercellular adhesion molecule 1 K469E gene polymorphism is associated with presence of skin lesions in Tunisian Behçet’s disease patients. Tissue Antigens 75:74–78

    Article  CAS  PubMed  Google Scholar 

  20. Ames PR, Steuer A, Pap A et al (2001) Thrombosis in Behçet’s disease: a retrospective survey from a single UK centre. Rheumatology 40:652–655

    Article  CAS  PubMed  Google Scholar 

  21. Bertina RM, Koeleman BP, Koster T et al (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369:64–67

    Article  CAS  PubMed  Google Scholar 

  22. Kujovich JL (2011) Factor V Leiden thrombophilia. Genet Med 13:1–16

    Article  CAS  PubMed  Google Scholar 

  23. Chamorro AJ, Marcos M, Hernández-García I et al (2013) Association of allelic variants of factor V Leiden, prothrombin and methylenetetrahydrofolate reductase with thrombosis or ocular involvement in Behçet’s disease: a systematic review and meta-analysis. Autoimmun Rev 12:607–616

    Article  CAS  PubMed  Google Scholar 

  24. Leung DW, Cachianes G, Kuang WJ et al (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    Article  CAS  PubMed  Google Scholar 

  25. Plate KH, Breiser G, Weich HA et al (1992) Vascular endothelial growth factor is a potential tumor angiogenesis factor in vivo. Nature 359:845–848

    Article  CAS  PubMed  Google Scholar 

  26. Ferrara N (1996) Vascular endothelial growth factor. Eur J Cancer 32A:2413–2422

    Article  CAS  PubMed  Google Scholar 

  27. Ferrara N, Davis-Smyth T (1997) The biology of vascular endothelial growth factor. Endocr Rev 18:4–25

    Article  CAS  PubMed  Google Scholar 

  28. Mor F, Quintana FJ, Cohen IR (2004) Angiogenesis-inflammation cross-talk: vascular endothelial growth factor is secreted by activated T cells and induces Th1 polarization. J Immunol 172:4618–4623

    CAS  PubMed  Google Scholar 

  29. Frassanito MA, Dammacco R, Cafforio P et al (1999) Th1 polarization of the immune response in Behçet’s disease: a putative pathogenetic role of interleukin-12. Arthritis Rheum 42:1967–1974

    Article  CAS  PubMed  Google Scholar 

  30. Ben Ahmed M, Houman H, Miled M et al (2004) Involvement of chemokines and Th1 cytokines in the pathogenesis of mucocutaneous lesions of Behçet’s disease. Arthritis Rheum 50:2291–2295

    Article  CAS  PubMed  Google Scholar 

  31. Cekmen M, Evereklioglu C, Er H et al (2003) Vascular endothelial growth factor levels are increased and associated with disease activity in patients with Behçet’s syndrome. Int J Dermatol 42:870–875

    Article  CAS  PubMed  Google Scholar 

  32. Salvarani C, Boiardi L, Casali B et al (2004) Vascular endothelial growth factor gene polymorphisms in Behçet’s disease. J Rheumatol 31:1785–1789

    CAS  PubMed  Google Scholar 

  33. Nam EJ, Han SW, Kim SU et al (2005) Association of vascular endothelial growth factor gene polymorphisms with Behçet disease in a Korean population. Hum Immunol 66:1068–1073

    Article  CAS  PubMed  Google Scholar 

  34. Kamoun M, Houman MH, Hamzaoui A et al (2008) Vascular endothelial growth factor gene polymorphisms and serum levels in Behçet’s disease. Tissue Antigens 72:581–587

    Article  CAS  PubMed  Google Scholar 

  35. Li H, Förstermann U (2000) Nitric oxide in the pathogenesis of vascular disease. J Pathol 190:244–254

    Article  CAS  PubMed  Google Scholar 

  36. Orem A, Vanizor B, Cimsit G et al (1999) Decreased nitric oxide production in patients with Behçet’s disease. Dermatology 198:33–36

    Article  CAS  PubMed  Google Scholar 

  37. Stuehr DJ (1997) Structure-function aspects in the nitric oxide synthases. Annu Rev Pharmacol Toxicol 37:339–359

    Article  CAS  PubMed  Google Scholar 

  38. Lee YH, Song GG (2012) Associations between eNOS polymorphisms and susceptibility to Behçet’s disease: a meta-analysis. J Eur Acad Dermatol Venereol 26:1266–1271

    Article  CAS  PubMed  Google Scholar 

  39. Meguro A, Inoko H, Ota M et al (2010) Genetics of Behçet’s disease inside and outside the MHC. Ann Rheum Dis 69:747–754

    Article  CAS  PubMed  Google Scholar 

  40. Chung YM, Yeh TS, Sheu MM et al (1990) Behçet’s disease with ocular involvement in Taiwan: a joint survey of six major ophthalmological departments. J Formos Med Assoc 89:413–417

    CAS  PubMed  Google Scholar 

  41. Mizuki N, Ohno S, Ando H et al (1997) A strong association between HLA-B*5101 and Behçet’s disease in Greek patients. Tissue Antigens 50:57–60

    Article  CAS  PubMed  Google Scholar 

  42. Kang EH, Kim JY, Takeuchi F et al (2011) Associations between the HLA-A polymorphism and the clinical manifestations of Behçet’s disease. Arthritis Res Ther 13:R49

    Article  CAS  PubMed  Google Scholar 

  43. Yabuki K, Ohno S, Mizuki N et al (1999) HLA class I and II typing of the patients with Behçet’s disease in Saudi Arabia. Tissue Antigens 54:273–277

    Article  CAS  PubMed  Google Scholar 

  44. Kaburaki T, Takamoto M, Numaga J et al (2010) Genetic association of HLA-A*2601 with ocular Behçet’s disease in Japanese patients. Clin Exp Rheumatol 28:S39–S44

    PubMed  Google Scholar 

  45. Verity DH, Wallace GR, Vaughan RW et al (1999) HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet’s disease. Tissue Antigens 54:264–272

    Article  CAS  PubMed  Google Scholar 

  46. Mizuki N, Ota M, Katsuyama Y et al (2001) HLA class I genotyping including HLA-B*51 allele typing in the Iranian patients with Behçet’s disease. Tissue Antigens 57:457–462

    Article  CAS  PubMed  Google Scholar 

  47. Kilmartin DJ, Finch A, Acheson RW (1997) Primary association of HLA-B51 with Behçet’s disease in Ireland. Br J Ophthalmol 81:649–653

    Article  CAS  PubMed  Google Scholar 

  48. Kera J, Mizuki N, Ota M et al (1999) 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 54:565–571

    Article  CAS  PubMed  Google Scholar 

  49. Pirim I, Atasoy M, Ikbal M et al (2004) HLA class I and class II genotyping in patients with Behçet’s disease: a regional study of eastern part of Turkey. Tissue Antigens 64:293–297

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  51. Mizuki N, Meguro A, Ota M et al (2010) Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet 42:703–706

    Article  CAS  PubMed  Google Scholar 

  52. Wallace GR, Kondeatis E, Vaughan RW et al (2007) IL-10 genotype analysis in patients with Behçet’s disease. Hum Immunol 68:122–127

    Article  CAS  PubMed  Google Scholar 

  53. Xavier JM, Shahram F, Davatchi F et al (2012) Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behçet’s disease. Arthritis Rheum 64:2761–2772

    Article  CAS  PubMed  Google Scholar 

  54. Jiang Z, Yang P, Hou S et al (2010) IL-23R gene confers susceptibility to Behçet’s disease in a Chinese Han population. Ann Rheum Dis 69:1325–1328

    Article  CAS  PubMed  Google Scholar 

  55. Mosmann TR, Coffman RL et al (1989) Thl and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann Rev Immunol 7:145–173

    Article  CAS  Google Scholar 

  56. Fiorentino DF, Zlotnik A, Vieira P et al (1991) IL-10 acts on the antigen presenting cell to inhibit cytokine production by Th1 cells. J Immunol 146:3444–3451

    CAS  PubMed  Google Scholar 

  57. Desai BB, Quinn PM, Wolitzky AG et al (1992) IL-12 receptor. II. distribution and regulation of receptor expression. J Immunol 148:3125–3132

    CAS  PubMed  Google Scholar 

  58. Rogge L, Barberis-Maino L, Biffi M et al (1997) Selective expression of an interleukin-12 receptor component by human T helper 1 cells. J Exp Med 185:825–831

    Article  CAS  PubMed  Google Scholar 

  59. Iwakura Y, Ishigame H (2006) The IL-23/IL-17 axis in inflammation. J Clin Invest 116:1218–1222

    Article  CAS  PubMed  Google Scholar 

  60. Steinman L (2009) Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nat Immunol 11:41–44

    Article  PubMed  Google Scholar 

  61. Khader SA, Gaffen SL, Kolls JK (2009) Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol 2:403–411

    Article  CAS  PubMed  Google Scholar 

  62. Isogai E, Ohno S, Kotake S et al (1990) Chemiluminescence of neutrophils from patients with Behçet’s disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora. Arch Oral Biol 35:43–48

    Article  CAS  PubMed  Google Scholar 

  63. Hou S, Yang Z, Du L et al (2012) Identification of a susceptibility locus in STAT4 for Behçet’s disease in Han Chinese in a genome-wide association study. Arthritis Rheum 64:4104–4113

    Article  CAS  PubMed  Google Scholar 

  64. Kirino Y, Bertsias G, Ishigatsubo Y et al (2013) Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 45:202–207

    Article  CAS  PubMed  Google Scholar 

  65. Kim ES, Kim SW, Moon CM et al (2012) Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behçet’s disease in Korean population. Life Sci 90:740–746

    Article  CAS  PubMed  Google Scholar 

  66. Watford WT, Hissong BD, Bream JH et al (2004) Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev 202:139–156

    Article  CAS  PubMed  Google Scholar 

  67. Nishikomori R, Usui T, Wu CY et al (2002) Activated STAT4 has an essential role in Th1 differentiation and proliferation that is independent of its role in the maintenance of IL-12R beta 2 chain expression and signaling. J Immunol 169:4388–4398

    CAS  PubMed  Google Scholar 

  68. Mathur AN, Chang HC, Zisoulis DG et al (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178:4901–4907

    CAS  PubMed  Google Scholar 

  69. Sun LD, Cheng H, Wang ZX et al (2010) Association analyses identify six new psoriasis susceptibility loci in the Chinese population. Nat Genet 42:1005–1009

    Article  CAS  PubMed  Google Scholar 

  70. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2, Strange A, Capon F et al (2010) A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 42:985–990

    Article  Google Scholar 

  71. Wellcome Trust Case Control Consortium; Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, Clayton DG et al (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–1337

    Article  Google Scholar 

  72. Evans DM, Spencer CC, Pointon JJ et al (2011) Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat Genet 43:761–767

    Article  CAS  PubMed  Google Scholar 

  73. Hou S, Xiao X, Li F et al (2012) Two-stage association study in Chinese Han identifies two independent associations in CCR1/CCR3 locus as candidate for Behçet’s disease susceptibility. Hum Genet 131:1841–1850

    Article  CAS  PubMed  Google Scholar 

  74. Diedrichs-Mohring M, Nelson PJ, Proudfoot AE et al (2005) The effect of the CC chemokine receptor antagonist Met-RANTES on experimental autoimmune uveitis and oral tolerance. J Neuroimmunol 164:22–30

    Article  PubMed  Google Scholar 

  75. Nibbs RJB, Salcedo TW, Campbell JDM et al (2000) C–C chemokine receptor 3 antagonism by the beta-chemokine macrophage inflammatory protein 4, a property strongly enhanced by an amino-terminal alanine-methionine swap. J Immunol 164:1488–1497

    CAS  PubMed  Google Scholar 

  76. Neote K, DiGregorio D, Mak JY et al (1993) Molecular cloning, functional expression, and signaling characteristics of a C–C chemokine receptor. Cell 72:415–425

    Article  CAS  PubMed  Google Scholar 

  77. Daugherty BL, Springer MS (1997) The beta-chemokine receptor genes CCR1 (CMKBR1), CCR2 (CMKBR2), and CCR3 (CMKBR3) cluster within 285 kb on human chromosome 3p21. Genomics 41:294–295

    Article  CAS  PubMed  Google Scholar 

  78. Lee YJ, Horie Y, Wallace GR et al (2013) Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behçet’s disease. Ann Rheum Dis 72:1510–1516

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Ophthalomology, Hokkaido University Graduate School of Medicine, N15, W7, Kitaku, Sapporo, Hokkaido, 060-8638, Japan

    Shigeaki Ohno

  2. Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan

    Akira Meguro & Nobuhisa Mizuki

  3. Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Turgut Ozal Millet caddesi, Istanbul, 34093, Turkey

    Ahmet Gül

  4. Department of Ophthalmology Health Sciences, University of Hokkaido, Ainosato 2-5, Kita-ku, Sapporo, Hokkaido, 002-8072, Japan

    Nobuyoshi Kitaichi

Authors
  1. Akira Meguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nobuhisa Mizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmet Gül
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nobuyoshi Kitaichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shigeaki Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigeaki Ohno .

Editor information

Editors and Affiliations

  1. SOD Patologia Medica, Center for Autoimmune Systemic Diseases, Behçet Center and Lupus Clinic - AOU Careggi, Florence, Italy

    Lorenzo Emmi

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Italia

About this chapter

Cite this chapter

Meguro, A., Mizuki, N., Gül, A., Kitaichi, N., Ohno, S. (2014). Behçet’s Syndrome According to Classical and Population Genetics. In: Emmi, L. (eds) Behçet's Syndrome. Rare Diseases of the Immune System. Springer, Milano. https://doi.org/10.1007/978-88-470-5477-6_4

Download citation

  • DOI: https://doi.org/10.1007/978-88-470-5477-6_4

  • Published:

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-5476-9

  • Online ISBN: 978-88-470-5477-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation