Abstract
Behçet’s disease (BD) is a multifactorial disease with a strong genetic background. Varying frequencies of patients with a positive family history for BD were described with a tendency for higher figures in the Middle Eastern, juvenile-onset and HLA-B51 positive patients. Sibling recurrence risk ratio (λs) was calculated to be 11.4–52.5 for BD patients in Turkey. 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 pathogenic mechanisms of HLA-B51 are still unknown, but it may include presentation of specific peptides to CD8+ cells and interaction with KIR3DL1 receptors. Although contribution of the HLA-B locus to the overall BD susceptibility was estimated to be 19%, other MHC associations including HLA-A26 and MICA*009 may have additive effects. Association studies also suggested several non-HLA disease susceptibility genes. However, only a few of them, including polymorphisms in the TNF, MEFV, ICAM1, and eNOS genes, were replicated in different ethnic groups. A linkage study in multicase families of Turkish origin revealed several possible susceptibility loci for BD with >3.0 nonparametric linkage scores at chromosome 12p12-13, 6p22-24, and 6q25-26. Recent genomewide association study using microsatellite markers in Japanese patients and controls confirmed the loci at 12p12 and 6q25, and it also suggested two additional loci at 3p12 and 22q11.22. Currently, results of genomewide association studies from different ethnic groups are being awaited to clarify the genetics of BD further.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Behçet’s disease
- Familial aggregation
- Sibling recurrence risk ratio (λs)
- HLA-B51
- MICA
- HLA-A26
- Linkage study
- Genomewide association study
Behçet’s disease (BD) is a systemic inflammatory disorder of unknown etiology. It is generally accepted as a multifactorial disease with a strong genetic background, and the disease manifestations are considered to be triggered by various environmental factors in genetically susceptible individuals [1, 2].
There are several clues supporting involvement of genetic factors in the pathogenesis of BD, which include familial aggregation, distinct geographic distribution, and its association with the HLA-B51 antigen.
Familial Aggregation
Although majority of BD patients are seen as sporadic cases, increased frequency of BD has long been noted among the relatives [3–16]. Varying frequencies of patients with a positive family history for BD were described in large series of patients, with a tendency for higher figures in the Middle Eastern patients compared to the patients from Asian and European countries [16, 17].
Gül and colleagues analyzed the sibling recurrence risk ratio (λs) for quantifying the familial aggregation in BD [17]. They calculated the sibling recurrence rate as 4.2 by taking into account only the immediately older sibling, or if an older sibling is not available, immediately younger sibling for evaluation. By using the prevalence rates of BD in Turkey, λs value was found to be 11.4–52.5 for BD [17]. This λs value was considered as strongly supporting the contribution of genetics to the multifactorial pathogenesis of BD.
Familial clustering was more frequently observed among juvenile-onset (<16) BD patients [18, 19]. Molinary and colleagues conducted a segregation analysis using the pedigree data of 106 BD cases. They included “possible” BD patients who had only two of the classical disease manifestations into the analysis, and they found a pattern compatible with autosomal recessive inheritance in pediatric BD subgroup, and no Mendelian pattern in adult-onset patients [19]. This study suggested a genetic heterogeneity with a higher impact of genetic load in juvenile BD cases [19].
Frequency of HLA-B51 was found to be higher in familial patients [11, 12]. However, presence of unaffected siblings with risk alleles also showed the complex nature of the disease indicating the contribution of other genes and/or environmental factors [11, 20]. A comparison of related pairs of patients according to their age at onset also supports involvement of both genetic and environmental factors in the pathogenesis [21, 22].
Another study from Turkey documented clues for genetic anticipation in the form of earlier disease onset in the second generation compared with their affected parents in 15 out of 18 familial cases studied [23]. However, no trinucleotide repeat expansion data are yet available to further support this observation.
No large series of twins concordant or discordant for BD were reported so far [24–26]. Therefore, large series of monozygotic and dizygotic twins are being awaited for heritability analysis to assess the relative contribution of genes and environment to the pathogenesis of BD.
Geographic Distribution
Epidemiology of BD has a distinct feature in terms of its geographic distribution. Prevalence of BD is much higher in an area extending from the Mediterranean basin to Japan, between 30° and 45° latitudes North, which overlaps with the ancient Silk Road [27]. There is no known specific environmental factor common along this route, but shared genetic factors may explain the clustering of BD cases. The frequency of BD-related HLA-B51 allele is higher in the healthy population living along this region, and distribution of HLA-B51 allele is suggested to play a role in the disease clustering [27, 28].
HLA-B51 and Other MHC Associations
BD is strongly associated with a class I major histocompatibility complex (MHC) allele, HLA-B51. This association was first reported in Japanese BD patients [28–30]. Association of HLA-B51 with BD was later confirmed in other ethnic groups, including those in which BD is seen very rarely [1, 2, 16, 27, 31–34].
No disease specific differences were observed in the sequence of HLA-B51 alleles between BD patients and healthy controls, neither in the coding region nor in the regulatory sequences [35, 36]. HLA-B51 is a split antigen of HLA-B5, and the other split antigen HLA-B52 has not been associated with BD despite some exceptional reports [37, 38]. HLA-B51 differs from HLA-B52 only by two aminoacids in the α1 helix. Asparagine and phenylalanine at positions 63 and 67 of the HLA-B51 molecule are replaced with glutamic acid and serine in the HLA-B52 at the same positions [39]. These two aminoacids are located at the B pocket of the antigen binding groove (Fig. 15.1). HLA-B51 allele can bind peptides with eight or nine aminoacids and a hydrophobic C-terminus [40]. Later studies suggested that B pocket can be occupied by small aminoacids alanine and proline, and changes in the B pocket can affect the motif of the peptides that can bind to HLA molecule [41]. Isoleucine and valine were identified as dominant anchor residues in the C-terminus of the refined peptide motif which binds to relatively small F pocket, and aminoacids making the F pocket are conserved in all HLA-B51 alleles [41].
HLA-B51 allele has 73 different subtypes (HLA-B*5101–B*5173), and they all share the same aminoacid sequence at the B pocket of the antigen binding groove except for B*5107 and B*5122. HLA-B*5101 is the dominant subtype of the B51 molecule, and molecular HLA-B51 typing in different ethnic groups suggests that HLA-B51 subtypes in BD patients are not different from those in healthy controls, with HLA-B*5101 and -B*5108 as the main subtypes [42–46].
Molecular typing of HLA-B51 molecules suggests that presentation of certain BD-associated peptides with its specific B and F pocket features might be one of the pathogenic mechanisms behind the susceptibility to BD. So far, only major histocompatibility complex class I chain-related gene A (MICA)-derived nonamer peptide (AAAAAIFVI) was shown to induce T cells in less than one-third of active HLA-B51 positive BD patients compared to none of the healthy controls [47].
HLA-B51, as a class I molecule, also interacts with a group of receptors expressed on natural killer (NK) cells, CD8+ and γδ T cells [48]. The killer immunoglobulin-like receptors (KIR), bind to conserved Bw4 epitopes at residues 77–83 of the α1-helix, which are shared by different allellic groups of HLA class I molecules. Engagement of these receptors can result in selective inhibition of NK or T cell mediated cytotoxicity. A relative predispositional effects analysis, conducted to search for weaker HLA-B associations with BD masked by strong HLA-B51 association, revealed a weak association of HLA-B*2702 with BD, which shares the same Bw4 motif with HLA-B51 [49]. Investigation of HLA-B51 interacting KIR3DL1/DS1 polymorphism documented the association of DL1/DL1 genotype with BD in Bw4-motif positive patients [50]. These preliminary studies support an alternative hypothesis that the pathogenic role of HLA-B51 may also include its interaction with KIR3DL1 molecules expressed on inflammatory cells.
HLA-B51-derived peptides can be presented by HLA class II molecules. HLA class I heavy chain misfolding as well as enhanced expression due to up-regulated immune response increase the possibility of class I-derived peptide presentation. Wildner and Thurau identified a polymorphic HLA-B sequence common in HLA-B27, -B51, and several other HLA-B alleles (B27PD), which shares aminoacid homologies with retinal soluble antigen (S-Ag)-derived peptide [51]. Kurhan-Yavuz and colleagues demonstrated increased T cell response against retinal S-Ag, retinal S-Ag derived peptide, and B27PD peptide in BD patients with posterior uveitis compared with those BD patients without eye disease or patients with non-BD anterior uveitis [52].
HLA-B51 is one of the slow folding MHC molecules [53]. However, there is no data showing the role of HLA-B51 folding problems and unfolded protein response in BD pathogenesis similar to the observations on HLA-B27 in ankylosing spondylitis animal models [54].
There is only one HLA-B*5101 heavy chain transgenic mouse model developed so far in investigating the direct role of HLA-B51 molecules in BD [55]. No manifestation typical for BD was observed in these transgenic animals. HLA-B51 transgenic animals showed an increased neutrophil activity following f-Met-Leu-Phe (fMLP) stimulation compared to HLA-B35 and nontransgenic mice [55]. A similar enhanced neutrophil activity was reported in HLA-B51 positive healthy individuals [11, 55, 56]. Extrapolating from the experience with HLA-B27 animal models, it is still needed to have a high heavy chain copy number transgenic animal models with and without human β2-microglobulin in different strains of mice and rats to explore the role of HLA-B51 in BD [57].
In addition to association studies, analysis of 12 multicase families confirmed the genetic linkage of the HLA-B locus to BD by using the transmission disequilibrium test [58]. Contribution of the HLA-B locus to the overall genetic susceptibility to BD was estimated to be 19% assuming multiplicative interaction between disease susceptibility loci [58]. This result supports the need for studies to look for other susceptibility loci.
Other MHC Associations
Linkage disequilibrium (LD) is high in the MHC, especially in the class I region with larger haplotype blocks [59]. It has long been discussed whether HLA-B51 has a direct role in the BD pathogenesis, or whether this strong association reflects LD with one or more susceptibility genes located close to the HLA-B locus (Fig. 15.2). The tumor necrosis factor (TNF) and lymphotoxin genes, which are located centromeric to HLA-B, were investigated first as possible candidate susceptibility genes. The analysis of the genomic segment between the TNF and HLA-B loci revealed a strong association of MICA gene with BD, which is located 46-kb centromeric to HLA-B [60]. The MICA gene *009 allele and its transmembrane region microsatellite polymorphism A6 allele were found to be significantly increased in BD patients [60–62]. Fine mapping of the region in different ethnic groups revealed HLA-B as the gene providing strongest association with BD, and all other associations including the MICA were resulting from strong LD with HLA-B51 [63]. However, it is still hard to rule out individual contribution of the MICA gene on an HLA-B51 haplotype to the BD susceptibility through its interaction with NK and γδ T cells.
Within the MHC region, no association with class II antigens was observed [64], but HLA-B51-associated LD extends to telomeric part of class I region. Weaker associations with HLA-Cw14, Cw15, and C*16 alleles [65, 66] and a negative association with nonclassical HLA-E*0101 and HLA-G*010101 alleles [67] were reported. Recent studies suggest a second HLA class I region association independent of HLA-B51 [68]. Meguro and colleagues reported the association of HLA-A26 allele and HLA-A*26-F*010101-G*010102 haplotype with BD even in HLA-B51 negative patients in Japan [68]. Association of HLA-A26 allele with BD was also observed in Taiwanese and Greek patients. These observations suggest that contribution of the MHC region to the BD susceptibility includes both HLA-B51 and other classical or nonclassical HLA associations with possible different pathogenic mechanisms.
Non-HLA Genes and Behçet’s Disease
As a complex disease, non-HLA genetic polymorphisms can also contribute to the BD susceptibility. For investigation of these susceptibility genes, a candidate gene approach was frequently preferred by investigators despite no clear evidence for utilizing this method in deciphering the pathogenic mechanisms of BD. Most of these association studies were carried out using small numbers of cases and controls with limited power. The list of non-HLA genes reported to be associated with BD are given in Table 15.1 [69–117]. Among the reported associations, only a few were replicated in different ethnic groups, including polymorphisms in the TNF, MEFV, ICAM1, and eNOS genes. None of these polymorphisms are disease specific, and they are considered to be contributing to a disease-specific inflammatory reaction.
Another approach for investigating complex disease susceptibility genes is screening of whole genome without a priori hypothesis about disease pathogenesis. A genomewide linkage screen using 193 individuals from 28 multicase BD families of Turkish origin with 83 affecteds revealed evidence for linkage to 15 non-HLA chromosomal regions: 1p36, 4p15, 5q12, 5q23, 6q16, 6q25–26, 7p21, 10q24, 12p12–13, 12q13, 16q12, 16q21–23, 17p13, 20q12–13, and Xq26–28 [118]. The linkage peak in the short arm of chromosome 6 (the maximum nonparametric linkage score 3.7) confirmed the strong association of HLA-B locus and also suggested another telomeric susceptibility loci [118, 119]. After the addition of further markers, high maximum nonparametric linkage scores were observed at chromosome 12p12-13 (3.94) and 6q25-26 (3.14).
Linkage studies in families are expected to identify rare, but penetrant genetic variations. However, genomewide association studies (GWAS) in large number of cases and controls can reveal common, but less penetrant polymorphisms affecting the disease susceptibility. A recent GWAS investigated 300 Japanese BD patients and 300 healthy controls with 23,465 microsatellite markers. This study identified six possible genomic regions, including two from the MHC region, one corresponding to HLA-B and the other to HLA-A [68]. Other non-HLA microsatellite markers suggested chromosomal regions 3p12 (D3S0186i), 6q25.1 (536G12Aa), 12p12.1 (D12S0645i), and 22q11.22 (D22S0104im) as possible genomic segments harboring disease susceptibility loci, two of which overlap with the findings of the previous linkage study [68]. Current GWAS approach enables us to analyze thousands of samples using chips for >300,000 single nucleotide polymorphisms in a relatively short time. Results of GWAS from different ethnic groups are eagerly being awaited to clarify the genetics of BD further.
References
Gül A (2001) Behçet’s disease: an update on the pathogenesis. Clin Exp Rheumatol 19(Suppl 24):S6–S12
Zierhut M, Mizuki N, Ohno S et al (2003) Immunology and functional genomics of Behçet’s disease. Cell Mol Life Sci 60:1903–1922
Fowler TJ, Humpston DJ, Nussey AM, Small M (1968) Behçet’s syndrome with neurological manifestations in two sisters. Br Med J 2:473–474
Mason RM, Barnes CG (1969) Behçet’s syndrome with arthritis. Ann Rheum Dis 28:95–103
Fadli ME, Youssef MM (1973) Neuro-Behçet’s syndrome in the United Arab Republic. Eur Neurol 9:76–89
Chajek T, Fainaru M (1975) Behçet’s disease: report of 41 cases and a review of the literature. Medicine (Baltimore) 54:179–196
Goolamali SK, Comaish JS, Hassanyeh F (1976) Familial Behçet’s syndrome. Br J Dermatol 95:637–642
Nahir M, Scharf Y, Gidoni O et al (1978) HL-A antigens in Behçet’s disease. A family study. Dermatologica 156:205–208
Abdel-Aziz AH, Fairburn EA (1978) Familial Behçet’s syndrome. Cutis 21:649–652
Dündar SV, Gencalp U, Simsek H (1985) Familial cases of Behçet’s disease. Br J Dermatol 113:319–321
Chajek-Shaul T, Pisanty S, Knobler H et al (1987) HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Behçet’s syndrome. Am J Med 83:666–672
Akpolat T, Koc Y, Yeniay I et al (1992) Familial Behçet’s disease. Eur J Med 1:391–395
Villanueva JL, Gonzalez-Dominguez J, Gonzalez-Fernandez R et al (1993) HLA antigen familial study in complete Behçet’s syndrome affecting three sisters. Ann Rheum Dis 52:155–157
Nishiura K, Kotake S, Ichiishi A, Matsuda H (1996) Familial occurrence of Behçet’s disease. Jpn J Ophthalmol 40:255–259
Nishiyama M, Nakae K, Umehara T (2001) A study of familial occurrence of Behçet’s disease with and without ocular lesions. Jpn J Ophthalmol 45:313–316
Fietta P (2005) Behçet’s disease: familial clustering and immunogenetics. Clin Exp Rheumatol 23(Suppl 38):S96–S105
Gül A, Inanc M, Ocal L et al (2000) Familial aggregation of Behçet’s disease in Turkey. Ann Rheum Dis 59:622–625
Treudler R, Orfanos CE, Zouboulis CC (1999) Twenty-eight cases of juvenile-onset Adamantiades-Behçet’s disease in Germany. Dermatology 199:15–19
Koné-Paut I, Geisler I, Wechsler B et al (1999) Familial aggregation in Behçet’s disease: high frequency in siblings and parents of pediatric probands. J Pediatr 135:89–93
Hayasaka S, Kurome H, Noda S (1994) HLA antigens in a Japanese family with Behçet’s disease. Graefes Arch Clin Exp Ophthalmol 232:589–590
Nishiyama M, Nakae K, Kuriyama T et al (2002) A study among related pairs of Japanese patients with familial Behçet’s disease: group comparisons by interval of disease onsets. J Rheumatol 29:743–747
Aronsson A, Tegner E (1983) Behçet’s syndrome in two brothers. Acta Derm Venereol 63:73–74
Fresko I, Soy M, Hamuryudan V et al (1998) Genetic anticipation in Behçet’s syndrome. Ann Rheum Dis 57:45–48
Hamuryudan V, Yurdakul S, Ozbakir F et al (1991) Monozygotic twins concordant for Behçet’s syndrome. Arthritis Rheum 34:1071–1072
Gül A, Inanç M, Ocal L et al (1997) HLA-B51 negative monozygotic twins discordant for Behçet’s disease. Br J Rheumatol 36:922–923
Kobayashi T, Sudo Y, Okamura S et al (2005) Monozygotic twins concordant for intestinal Behçet’s disease. J Gastroenterol 40:421–425
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
Ohno S, Ohguchi M, Hirose S et al (1982) Close association of HLA-Bw51 with Behçet’s disease. Arch Ophthalmol 100:1455–1458
Ono S, Aoki K, Sugiura S et al (1973) HL-A5 and Behçet’s disease. Lancet 2:1383–1384
Ono S, Nakayama E, Sugiura S et al (1975) Specific histocompatibility antigens associated with Behçet’s disease. Am J Ophthalmol 80:636–641
Kilmartin DJ, Finch A, Acheson RW (1997) Primary association of HLA-B51 with Behçet’s disease in Ireland. Br J Ophthalmol 81:649–653
Ambresin A, Tran T, Spertini F, Herbort C (2002) Behçet’s disease in Western Switzerland: epidemiology and analysis of ocular involvement. Ocul Immunol Inflamm 10:53–63
Pipitone N, Boiardi L, Olivieri I et al (2004) Clinical manifestations of Behçet’s disease in 137 Italian patients: results of a multicenter study. Clin Exp Rheumatol 22(Suppl 36):S46–S51
Bettencourt A, Pereira C, Carvalho L et al (2008) New insights of HLA class I association to Behçet’s disease in Portuguese patients. Tissue Antigens 72:379–382
Sano K, Yabuki K, Imagawa Y et al (2001) The absence of disease-specific polymorphisms within the HLA-B51 gene that is the susceptible locus for Behçet’s disease. Tissue Antigens 58:77–82
Takemoto Y, Naruse T, Namba K et al (2008) Re-evaluation of heterogeneity in HLA-B*510101 associated with Behçet’s disease. Tissue Antigens 72:347–353
Arber N, Klein T, Meiner Z et al (1991) Close association of HLA-B51 and B52 in Israeli patients with Behçet’s syndrome. Ann Rheum Dis 50:351–353
Sugisaki K, Saito R, Takagi T et al (2005) HLA-B52-positive vasculo-Behçet’s disease: usefulness of magnetic resonance angiography, ultrasound study, and computed tomographic angiography for the early evaluation of multiarterial lesions. Mod Rheumatol 15:56–61
Falk K, Rötzschke O, Takiguchi M et al (1995) Peptide motifs of HLA-B51, -B52 and -B78 molecules, and implications for Behçet’s disease. Int Immunol 7:223–228
Sakaguchi T, Ibe M, Miwa K et al (1997) Predominant role of N-terminal residue of nonamer peptides in their binding to HLA-B* 5101 molecules. Immunogenetics 46:245–248
Lemmel C, Rammensee H-G, Stevanovic S (2003) Peptide motif of HLA-B*5101 and the linkage to Behçet’s disease. In: Zierhut M, Ohno S (eds) Immunology of Behçet’s disease. Swets & Zeitlinger, Lisse, pp 127–137
Mizuki N, Inoko H, Ando H et al (1993) Behçet’s disease associated with one of the HLA-B51 subantigens, HLA-B* 5101. Am J Ophthalmol 116:406–409
Mizuki N, Ota M, Katsuyama Y et al (2002) 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 59:118–121
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
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
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
Yasuoka H, Okazaki Y, Kawakami Y et al (2004) Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet’s disease. Arthritis Rheum 50:3658–3662
Martin MP, Gao X, Lee J-H et al (2002) Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 31:429–434
Gül A, Uyar FA, Inanç M et al (2002) A weak association of HLA-B*2702 with Behçet’s disease. Genes Immun 3:368–372
Duymaz-Tozkir J, Uyar A, Norman PJ et al (2008) Distribution of killer immunoglobulin-like receptor 3DL1/3DS1 alleles in Behçet’s disease. Arthritis Rheum 58(Suppl):S855
Wildner G, Thurau SR (1994) 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 24:2579–2585
Kurhan-Yavuz S, Direskeneli H, Bozkurt N et al (2000) 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 120:162–166
Hill A, Takiguchi M, McMichael A (1993) Different rates of HLA class I molecule assembly which are determined by amino acid sequence in the alpha 2 domain. Immunogenetics 37:95–101
Turner MJ, Sowders DP, DeLay ML et al (2005) HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175:2438–2448
Takeno M, Kariyone A, Yamashita N et al (1995) Excessive function of peripheral blood neutrophils from patients with Behçet’s disease and from HLA-B51 transgenic mice. Arthritis Rheum 38:426–433
Sensi A, Gavioli R, Spisani S et al (1991) HLA B51 antigen associated with neutrophil hyper-reactivity. Dis Markers 9:327–331
Taurog JD, Maika SD, Satumtira N et al (1999) Inflammatory disease in HLA-B27 transgenic rats. Immunol Rev 169:209–223
Gül A, Hajeer AH, Worthington J et al (2001) Evidence for linkage of the HLA-B locus in Behçet’s disease, obtained using the transmission disequilibrium test. Arthritis Rheum 44(1):239–240
Miretti MM, Walsh EC, Ke X et al (2005) A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am J Hum Genet 76:634–646
Mizuki N, Ota M, Kimura M et al (1997) Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet’s disease. Proc Natl Acad Sci U S A 94:1298–1303
Hughes EH, Collins RW, Kondeatis E et al (2005) Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Behçet’s disease in Caucasian patients. Tissue Antigens 66:195–199
Mizuki N, Meguro A, Tohnai I et al (2007) Association of major histocompatibility complex Class I chain-related Gene A and HLA-B alleles with Behçet’s disease in Turkey. Jpn J Ophthalmol 51:431–436
Mizuki N, Ota M, Yabuki K et al (2000) Localization of the pathogenic gene of Behçet’s disease by microsatellite analysis of three different populations. Invest Ophthalmol Vis Sci 41:3702–3708
Mizuki N, Ohno S, Tanaka H et al (1992) Association of HLA-B51 and lack of association of class II alleles with Behçet’s disease. Tissue Antigens 40:22–30
Mizuki N, Ohno S, Ando H et al (1996) HLA-C genotyping of patient with Behçet’s disease in the Japanese population. Hum Immunol 50:47–53
Sanz L, González-Escribano F, de Pablo R et al (1998) HLA-Cw*1602: a new susceptibility marker of Behçet’s disease in southern Spain. Tissue Antigens 51:111–114
Park KS, Park JS, Nam JH et al (2007) HLA-E*0101 and HLA-G*010101 reduce the risk of Behçet’s disease. Tissue Antigens 69:139–144
Meguro A, Inoko H, Ota M, et al (2009) Genetics of Behçet’s disease inside and outside the MHC. Ann Rheum Dis 69:747–754
Ahmad T, Wallace GR, James T et al (2003) Mapping the HLA association in Behçet’s disease: a role for tumor necrosis factor polymorphisms? Arthritis Rheum 48:807–813
Akman A, Sallakci N, Coskun M et al (2006) TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behçet’s disease. Br J Dermatol 155:350–356
Park K, Kim N, Nam J et al (2006) Association of TNFA promoter region haplotype in Behçet’s disease. J Korean Med Sci 21:596–601
Kamoun M, Chelbi H, Houman MH et al (2007) Tumor necrosis factor gene polymorphisms in Tunisian patients with Behçet’s disease. Hum Immunol 68:201–205
Karasneh J, Hajeer AH, Barrett J et al (2003) Association of specific interleukin 1 gene cluster polymorphisms with increased susceptibility for Behçet’s disease. Rheumatology (Oxford) 42:860–864
Chang HK, Jang WC, Park SB et al (2005) Association between interleukin 6 gene polymorphisms and Behçet’s disease in Korean people. Ann Rheum Dis 64:339–340
Lee EB, Kim JY, Zhao J et al (2007) Haplotype association of IL-8 gene with Behçet’s disease. Tissue Antigens 69:128–132
Wallace GR, Kondeatis E, Vaughan RW et al (2007) IL-10 genotype analysis in patients with Behçet’s disease. Hum Immunol 68:122–127
Yanagihori H, Oyama N, Nakamura K et al (2006) Role of IL-12B promoter polymorphism in Adamantiades-Behçet’s disease susceptibility: an involvement of Th1 immunoreactivity against Streptococcus Sanguinis antigen. J Invest Dermatol 126:1534–1540
Jang WC, Nam YH, Ahn YC et al (2008) Interleukin-17F gene polymorphisms in Korean patients with Behçet’s disease. Rheumatol Int 29:173–178
Lee YJ, Kang SW, Park JJ et al (2006) Interleukin-18 promoter polymorphisms in patients with Behçet’s disease. Hum Immunol 67:812–818
Mojtahedi Z, Ahmadi SB, Razmkhah M et al (2006) Association of chemokine receptor 5 (CCR5) delta32 mutation with Behçet’s disease is dependent on gender in Iranian patients. Clin Exp Rheumatol 24(Suppl 42):S91–S94
Ateş O, Dalyan L, Hatemi G et al (2009) Genetic susceptibility to Behçet’s syndrome is associated with NRAMP1 (SLC11A1) polymorphism in Turkish patients. Rheumatol Int 29:787–791
Kim SK, Jang WC, Park SB et al (2006) SLC11A1 gene polymorphisms in Korean patients with Behçet’s disease. Scand J Rheumatol 35:398–401
Ben Dhifallah I, Chelbi H, Braham A et al (2009) CTLA-4 +49A/G polymorphism is associated with Behçet’s disease in a Tunisian population. Tissue Antigens 73(3):213–217
Park KS, Baek JA, Do JE et al (2009) CTLA4 gene polymorphisms and soluble CTLA4 protein in Behçet’s disease. Tissue Antigens 74:222–227
Wang H, Nakamura K, Inoue T et al (2004) Mannose-binding lectin polymorphisms in patients with Behçet’s disease. J Dermatol Sci 36:115–117
Park KS, Min K, Nam JH et al (2005) Association of HYPA haplotype in the mannose-binding lectin gene-2 with Behçet’s disease. Tissue Antigens 65:260–265
Chen X, Katoh Y, Nakamura K et al (2006) Single nucleotide polymorphisms of Ficolin 2 gene in Behçet’s disease. J Dermatol Sci 43:201–205
Hou S, Yang P, Du L et al (2008) SUMO4 gene polymorphisms in Chinese Han patients with Behçet’s disease. Clin Immunol 129:170–175
Li K, Zhao M, Hou S, Du L et al (2008) Association between polymorphisms of FCRL3, a non-HLA gene, and Behçet’s disease in a Chinese population with ophthalmic manifestations. Mol Vis 14:2136–2142
Seo J, Park JS, Nam JH et al (2007) Association of CD94/NKG2A, CD94/NKG2C, and its ligand HLA-E polymorphisms with Behçet’s disease. Tissue Antigens 70:307–313
Baranathan V, Stanford MR, Vaughan RW et al (2007) The association of the PTPN22 620W polymorphism with Behçet’s disease. Ann Rheum Dis 66:1531–1533
Gunesacar R, Erken E, Bozkurt B et al (2007) Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behçet’s disease. Int J Immunogenet 34:45–49
Meguro A, Ota M, Katsuyama Y et al (2008) Association of the toll-like receptor 4 gene polymorphisms with Behçet’s disease. Ann Rheum Dis 67:725–727
Horie Y, Meguro A, Ota M et al (2009) Association of TLR4 polymorphisms with Behçet’s disease in a Korean population. Rheumatology (Oxford) 48:638–642
Touitou I, Magne X, Molinari N et al (2000) MEFV mutations in Behçet’s disease. Hum Mutat 16:271–272
Atagunduz P, Ergun T, Direskeneli H (2003) MEFV mutations are increased in Behçet’s disease (BD) and are associated with vascular involvement. Clin Exp Rheumatol 21(Suppl 30):S35–S37
Imirzalioglu N, Dursun A, Tastan B et al (2005) MEFV gene is a probable susceptibility gene for Behçet’s disease. Scand J Rheumatol 34:56–58
Rabinovich E, Shinar Y, Leiba M et al (2007) Common FMF alleles may predispose to development of Behçet’s disease with increased risk for venous thrombosis. Scand J Rheumatol 36:48–52
Ayesh S, Abu-Rmaileh H, Nassar S et al (2008) Molecular analysis of MEFV gene mutations among Palestinian patients with Behçet’s disease. Scand J Rheumatol 37:370–374
Amoura Z, Dodé C, Hue S et al (2005) Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behçet’s disease. Arthritis Rheum 52:608–611
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
Boiardi L, Salvarani C, Casali B et al (2001) Intercellular adhesion molecule-1 gene polymorphisms in Behçet’s disease. J Rheumatol 28:1283–1287
Kim EH, Mok JW, Bang DS et al (2003) Intercellular adhesion molecule-1 polymorphisms in Korean patients with Behçet’s disease. J Korean Med Sci 18:415–418
Chmaisse HN, Fakhoury HA, Salti NN, Makki RF (2006) The ICAM-1 469 T/C gene polymorphism but not 241 G/A is associated with Behçet’s disease in the Lebanese population. Saudi Med J 27:604–607
Salvarani C, Boiardi L, Casali B et al (2002) Endothelial nitric oxide synthase gene polymorphisms in Behçet’s disease. J Rheumatol 29:535–540
Kim JU, Chang HK, Lee SS et al (2003) Endothelial nitric oxide synthase gene polymorphisms in Behçet’s disease and rheumatic diseases with vasculitis. Ann Rheum Dis 62:1083–1087
Karasneh JA, Hajeer AH, Silman A et al (2005) Polymorphisms in the endothelial nitric oxide synthase gene are associated with Behçet’s disease. Rheumatology (Oxford) 44:614–617
Ben Dhifallah I, Houman H, Khanfir M, Hamzaoui K (2008) Endothelial nitric oxide synthase gene polymorphism is associated with Behçet’s disease in Tunisian population. Hum Immunol 69:661–665
Gül A, Ozbek U, Oztürk C et al (1996) Coagulation factor V gene mutation increases the risk of venous thrombosis in Behçet’s disease. Br J Rheumatol 35:1178–1180
Verity DH, Vaughan RW, Madanat W et al (1999) Factor V Leiden mutation is associated with ocular involvement in Behçet’s disease. Am J Ophthalmol 128(3):352–356
Mammo L, Al-Dalaan A, Bahabri SS, Saour JN (1997) Association of factor V Leiden with Behçet’s disease. J Rheumatol 24:2196–2198
Gül A, Aslantas AB, Tekinay T et al (1999) Procoagulant mutations and venous thrombosis in Behçet’s disease. Rheumatology (Oxford) 38:1298–1299
Ricart JM, Vayá A, Todolí J et al (2006) Thrombophilic risk factors and homocysteine levels in Behçet’s disease in eastern Spain and their association with thrombotic events. Thromb Haemost 95(4):618–624
Nakao K, Isashiki Y, Sonoda S et al (2007) Nitric oxide synthase and superoxide dismutase gene polymorphisms in Behçet’s disease. Arch Ophthalmol 125:246–251
Tursen U, Tamer L, Api H et al (2007) Cytochrome P450 polymorphisms in patients with Behçet’s disease. Int J Dermatol 46:153–156
Yen JH, Tsai WC, Lin CH et al (2004) Cytochrome P450 1A1 and manganese superoxide dismutase gene polymorphisms in Behçet’s disease. J Rheumatol 31:736–740
Tamer L, Tursen U, Eskandari G et al (2005) N-acetyltransferase 2 polymorphisms in patients with Behçet’s disease. Clin Exp Dermatol 30:56–60
Karasneh J, Gül A, Ollier WE et al (2005) Whole-genome screening for susceptibility genes in multicase families with Behçet’s disease. Arthritis Rheum 52:1836–1842
Gül A, Hajeer AH, Worthington J et al (2001) Linkage mapping of a novel susceptibility locus for Behçet’s disease to chromosome 6p22-23. Arthritis Rheum 44:2693–2696
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Gül, A., Ohno, S. (2010). Genetics of Behçet’s Disease. In: Yazıcı, Y., Yazıcı, H. (eds) Behçet’s Syndrome. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-5641-5_15
Download citation
DOI: https://doi.org/10.1007/978-1-4419-5641-5_15
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-5640-8
Online ISBN: 978-1-4419-5641-5
eBook Packages: MedicineMedicine (R0)