Open access peer-reviewed chapter

Genetics of Behçet’s Disease

Written By

Xiaodong Zhou and Yan Deng

Submitted: February 19th, 2019 Reviewed: May 27th, 2019 Published: August 30th, 2019

DOI: 10.5772/intechopen.87080

Chapter metrics overview

970 Chapter Downloads

View Full Metrics


Behçet’s disease (BD) is a chronic refractory multi-system autoimmune disorder with a strong genetic component. Like many other human complex diseases, multiple genes with polymorphisms have been associated with BD. These genes encode proteins involved mainly in immune regulation and inflammation and some in transcriptional activation and post-translational modification. Understanding the genetic association of these genes with BD may provide insight into the pathogenesis and for development of new, targeted therapies for this human complex disease.


  • Behçet’s disease
  • genetic
  • HLA region
  • interleukin family
  • inflammation and autoimmunity
  • transcriptional activation

1. Introduction

Behçet’s disease (BD) is a chronic inflammatory disorder with unclear etiology. It can affect a variety of organs characterized by refractory ulcers in genitals and mouth, uveitis, skin lesions, and manifestations in joints, gastrointestinal tract, kidneys, lungs, and cardiovascular and central nervous systems [1]. BD has distinctive geographical distribution, and it is found primarily in populations along the ancient Silk Route from the Mediterranean region transiting through Central Asia to East Asia [2]. The reported prevalence of BD varies between Western (0.12–7.5 per 100,000) [3] and Eastern countries (6.3–14 per 100,000) [4]. Turkey has the highest incidence of BD in general population (80–420 per 100,000) [5, 6, 7]. A family history of BD significantly increases the risk at a rate of 31.2% [8], which indicates a strong genetic contribution to the disease by comparing to general population. Men are more commonly affected in Middle Eastern countries, but that appears opposite in USA, Brazil, Israel, and Korea [9]. The first reported genetic association of BD was found in the human leukocyte antigen (HLA) region, or the major histocompatibility complex (MHC) on chromosome 6 [10]. HLA-B51 confers the strongest genetic risk to BD [11]. Multiple other genetic factors outside the HLA region have also been identified. The following are the categorized genes associated with BD reported from 1973 to January 2019.


2. HLA and HLA-related genes

2.1 HLA

HLA genes are among the most polymorphic genes in the human genome, and they are associated with almost all autoimmune diseases. HLA-B51 is the strongest risk allele for BD, which has been replicated in almost all studied populations [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. The population attributable risk (PAR) of HLA-B5/B51 was estimated as 52.2% for BD patients in Southern Europe, 49.9% in Middle East/North Africa, 44.4% in East Asia, and 31.7% in Northern Europe [23]. Other HLA alleles including BD-risk HLA-A02, -A24, -A26, -A31, -B27, -B57, and BD-protective HLA-A03, -B15, -B35, -B49, -B58 were reported in different populations [22, 24, 25, 26, 27, 28, 29].

Certain HLA alleles were also associated with clinical outcomes of BD. BD patients carrying HLA-A26:01 have a poor visual prognosis in Japan [30] and a high incidence of posterior uveitis in Korea [31]. Some HLA alleles were associated with lesions of specific organs in the Korean and Japanese patients, such as HLA-A26:01 with uveitis, HLA-A02:07 with skin lesions and arthritis, and -A30:04 with vascular lesions, genital ulcers, and a positive pathergy test [32]. These findings suggest that specific HLA alleles are likely used as genetic markers for subclassification and/or prognostic evaluation of BD patients.


The class II major histocompatibility complex transactivator (CIITA) is a transcriptional activator that acts as a master regulator of the HLA class II genes and some other immune-mediating genes [33, 34]. A single nucleotide polymorphism (SNP) of the CIITA gene rs12932187 with G allele and GG genotype appeared to be a risk factor to Chinese BD, and the GG carriers were correlated with a higher expression of the CIITA gene, and with a lower level of IL-10 protein from the peripheral blood mononuclear cells (PBMC) in response to lipopolysaccharide (LPS) [35].

2.3 ERAP1

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an essential enzyme to trim peptides in the ER for optimized binding by MHC class I molecules. The association between ERAP1 and BD was first reported in a Turkish population and was replicated in a Chinese cohort, in which the SNPs rs10050860 and rs17482078 of the ERAP1 gene encoding variants of amino acids Asp575Asn and Arg725Gln, respectively, conferred risk to BD [36, 37]. Further analysis of the association indicated that the ERAP1 variant Arg725Gln may interact with the HLA-B51 protein to confer susceptibility to BD [36, 38]. Moreover, the expression of ERAP1 was found to be significantly lower in active BD patients [37], and the patients carrying AA and CC genotype of the ERAP1 SNP rs1065407 and rs10050860, respectively, showed a higher expression level of the ERAP1 gene than the patients carrying AC or CC and CT or TT genotypes of the SNPs, respectively, in response to LPS [37, 38].

2.4 MICA

The major histocompatibility complex class I chain-related gene A (MICA), located on the centromeric side of the HLA-B gene on chromosome 6, is highly polymorphic [39]. It functions in immune activation under cellular stress conditions, such as infections, tissue injury, pro-inflammatory signals, and malignant transformation [40]. There have been more than 100 MICA alleles identified according to its overall sequence variations. In addition, the codon 295 of the MICA gene has a tri-nucleotide microsatellite polymorphism (GCT)n that is designated as An (A4, A5, A6, A9) allele, and a five repetition of GCT may coexist with a guanosine insertion that is designated as A5.1 [41].

MICA*009 and *019 alleles were associated with BD in a Spanish population [42], and MICA-A6 allele with Japanese and Korean BD patients [43, 44, 45]. The latter appeared to be independent from the potential linkage disequilibrium (LD) effect of HLA-B51 according to the Korean study [45].

On the other hand, MICA-A5.1 demonstrated a negative correlation with ocular lesions and iridocyclitis in BD patients [45, 46]. MICA-A9 was associated with BD patients who had less severe complications including uveitis, thrombosis, and neurological and intestinal involvement [47].


3. Interleukin (IL) family genes

3.1 IL-10

IL-10 is a cytokine with anti-inflammatory properties, which plays critical roles in modulating immune response and preventing inflammatory and autoimmune pathologies [48, 49]. The SNP rs1800871 of the IL10 promoter region was first found in an association with BD in the UK and Middle Eastern (ME) cohorts [50]. The genome-wide association studies (GWAS) revealed multiple BD-associated SNPs (rs1518111, rs1554286, rs1800871, and rs1800872) of the IL-10 in Chinese, Turkey, Japanese, and Korean cohorts [51, 52, 53].

3.2 IL-12A, IL-23R, and IL-12RB2

IL-12A is a gene which encodes for IL-35 that is a subunit of the heterodimeric cytokines IL-12 (encoded by IL-12B) and IL-35. IL-35 binds to a heterodimeric IL-12 receptor (IL-12R) that consists of IL-12Rβ1 (encoded by IL-12RB1) and IL-12Rβ2 (encoded by IL-12RB2) [54], and it impacts on activation of NK cells and polarization of the Th1 pathway through differentiation from naïve CD4+ T cells [55, 56]. The association of the IL-12A variants rs1780546 and rs17810458 with BD was found in the Turkish and European cohorts [36, 57].

IL-23 is a member of the IL-12 cytokine family. It plays crucial roles in the development process of the Th17 cells [58]. The receptor for IL-23 is composed of two subunits encoded by the IL-23R and the IL-12RB1 genes [59], and it plays a key role in neutrophil inflammation and in autoimmune diseases [60].

A significant association (reaching a GWAS p value) of the IL-23R gene with BD was found at the SNP rs11209026 (Gly149Arg) in Japanese, and at the SNP rs76418789 (Arg381Gln) in Turkish cohort [61]. The association between BD and the IL-23R/IL-12RB2 genes appeared to be consistent in multiple reports with different populations including Turkey [52], Japanese [53], Han Chinese [62, 63], Iranian [64], Western Algeria [65], and Korean [66].

3.3 IL-33

IL-33 is a member of the IL-1 family that drives production of Th2-associated cytokines [67]. A small Iranian cohort of BD patients showed a significantly higher prevalence of the IL-33 SNP rs1342326 T/G, and this genotype was also associated with higher IL-33 expression in the PBMC of the BD patients [68].


4. Genes involved in inflammation and autoimmunity

4.1 MEFV

The Mediterranean fever (MEFV) protein, also named pyrin is an important regulator of innate immunity [69]. Of noting, familial Mediterranean fever and BD share inflammatory nature and high prevalence in Middle Eastern and Mediterranean populations. Genetically, the MEFV SNPs rs61752717 Met694Val, rs28940580 Met680Ile, and rs3743930 Glu148Gln confer risk to both diseases [61, 70, 71, 72, 73, 74]. Moreover, Met694Val and Met680Ile of the MEFV gene were also associated with greater responsiveness to bacterial products [72, 73].

4.2 IRF8

Interferon regulatory factor (IRF) 8 is a member of the interferon (IFN) regulatory factor (IRF) family, and it acts as a transcription factor to regulate the development and function of a variety of immune cells. In particular, it regulates expression of type I IFN stimulated genes [75], and interacts with the Th17 master transcription factor, ROR-γt to inhibit Th17 cell differentiation [76]. In a study with Chinese cohort, the IRF8 SNPs rs17445836 and rs11642873 were associated with BD, and they appeared to regulate IRF8 expression and corresponding cytokine production [77]. In another study with multiple cohorts including Turkish, Iranian, and Japanese patients, three other BD-associated SNPs (rs11117433, rs142105922 and rs7203487) of the IRF8 gene were reported [78].


TNF-α-induced protein 3 (TNFAIP3) is a ubiquitin-modifying enzyme A20 that regulates inflammation through NF-κB signaling pathway, and it can be induced by TNF, Toll-like receptors (TLRs), IL-1R, and NOD2 signaling [79, 80, 81, 82]. The reports of genetic association between TNFAIP3 and BD appeared conflict in studies of Chinese and European populations. In the former, the TNFAIP3 SNPs (rs9494885, rs10499194 and rs7753873) were associated with BD [83], but were not replicated in the latter [84]. On the other hand, a Japanese study of familial BD indicated that a missense mutation C243Y in A20/TNFAIP3 was likely responsible for an increased production of some inflammatory cytokines by reduced suppression of NF-κB activation [85].

4.4 REL

The REL gene encodes for c-Rel, a member of the NF-κB family of transcription factors. It may play important roles in regulation of immune activity [86, 87]. A Chinese study indicated that the REL SNPs rs842647 may confer susceptibility to BD, and the allele C of this SNP was also associated with skin lesions in BD patients [88].

4.5 TLR2 and TLR4

Toll-like receptors (TLR) are transmembrane proteins that mediate innate immunity by recognizing pathogen molecules [89]. TLR2 and TLR4 are two members of the TLR, and they may transduce response to different types of pathogens (e.g., in macrophages, the former mainly for Gram-positive bacteria and the latter for Gram-negative). The TLR2 SNP rs2289318 (C allele and genotype CC) and rs3804099 (CT genotype) were associated with ocular BD in a Chinese cohort [90]. The associations of the TLR4 gene with BD are conflict in different reports. It was found in Japanese [91], Korea [92] and Turkish cohorts [66], but not in Italian [93], Tunisian [94], and Chinese cohorts [95]. Of note, two BD protective TLR4 variants identified in the Turkish cohort, p.Asp299Gly (rs4986790) and p.Thr399Ile (rs4986791) were associated with hyporesponsiveness to endotoxin [96].

4.6 NOD1 and NOD2

Nucleotide-binding oligomerization domain (NOD)-like receptors are intracellular proteins that regulate innate immune response. NOD1 and NOD2 proteins are two members of the NOD family, and they play important roles in initiating inflammation in response to microbial components [97, 98]. In a Chinese report, the minor allele (G) of the NOD1 SNP rs2075818 was protective from BD [35]. Multiple studies indicated that a Crohn’s disease-associated polymorphism, Arg702Trp of the NOD2 rs2066844 was also protective from BD [61, 99, 100].

4.7 CCR1 and CCR3

CCR1 and CCR3 proteins are two C-C motif chemokine receptor (CCR) family members. They mediate signal transduction within cells in response to pathogens, and they are critical for the recruitment of effector immune cells to the site of inflammation, and for maintaining homeostasis of the immune system [101]. The CCR1 and 3 genes are clustered together on chromosome 3p. The Several SNPs at CCR1-CCR3 locus were associated with BD including rs7616215 in Turkish [40] and rs13084057, rs13092160 and rs13075270 in Chinese Cohorts [102]. In addition, the CCR1 gene was individually associated with BD in multiple cohorts including Turkish, Japanese, and Iranian cohorts [36, 103]. Functional studies indicated that CCR1 gene expression in primary human monocytes carrying the BD-risk allele was reduced along with a weaker activity of monocyte chemotaxis [36].


GTPase of the immunity-associated protein (GIMAP) family is a group of newly identified proteins. Although their functions are still poorly characterized, it is believed that they are lymphocyte signaling molecules, and they are also involved in survival and apoptosis of T cells and some other cell types [104, 105]. A GIMAP cluster including SNPs in GIMAP1 (rs2286900), GIMAP2 (rs10266069 and rs10256482), and GIMAP4 (rs1916012, rs1522596, and rs1608157) was associated with BD in a study of Korean and Japanese populations [106], but it failed in a replication study of European cohort [107].

4.9 KLRC4

Killer cell lectin-like receptor subfamily C, member 4 (KLRC4) is a member of NKG2 receptor family that regulates NK cell function. The association of the KLRC4 gene and BD was first suggested in the GWAS of Turkish and Japanese cohorts [36], and then replicated in the independent study of an Iranian cohort [103].


5. Genes involved in transcriptional activation of immune regulation

5.1 STAT4

Signal transducer and activator of transcription-4 (STAT4) is a transcription factor that activates gene expression involved in functional regulation and differentiation of T-helper cells, natural killer (NK) cells, mast cells, and dendritic cells [108]. It modulates differentiation of naïve T cells into Th1 and Th17 cells [56, 109, 110].

The association between the STAT4 gene and BD appeared to be consistent in multiple independent studies including Han Chinese [107], Korean, Turkish, and Iranians [36, 103]. Functional studies indicated that the risk allele A of the STAT4 SNP rs897200 was correlated with the increased mRNA level of the STAT4 gene, and with the increased gene and protein expression of IL-17, as well as with BD patients who have a higher clinical severity score [111].

5.2 NCOA5

Nuclear receptor coactivator-5 (NCOA5) protein regulates nuclear receptor subfamily 1 group D member 2 (NR1D2) and estrogen receptor 1 and 2 (ESR1 and ESR2) [112, 113]. The NCOA5 gene SNP rs2903908 was associated with BD patients, especially those affected with genital ulceration and uveitis in the Finland and the Turkish cohorts [114].

5.3 FOXP3

FOXP3 (forkhead box P3), also known as scurfin, is a member of the FOX protein family of transcription factors. It regulates the development and function of T regulatory (Treg) cells [115, 116]. The FOXP3 SNP rs3761548 was associated with BD in the North-Western Iranian population [117]. In addition, a low copy number variant (CNV) of the FOXP3 gene was reported to confer risk to female BD patients in a Chinese cohort [118].


6. Other genes

6.1 PSORS1C1

Psoriasis susceptibility 1 candidate 1 (PSORS1C1) is poorly characterized in terms of its biological function. It is initially recognized as a susceptibility locus to psoriasis [119] and psoriatic arthritis [120]. Recent studies indicated that it is also a shared genetic factor, especially with SNP rs12525170, in other autoimmune diseases including systemic sclerosis [121], Crohn’s disease [122], and BD [122]. Therefore, it may play important roles in the pathogenesis of autoimmunity [123, 124].

6.2 FUT2

Fucosyltransferase 2 (FUT2) is involved in synthesis of the H antigen, the precursor of the ABO-histo-blood group antigen in body fluids, and on the intestinal mucosa [125]. The association between the FUT2 gene (rs632111, rs601338, rs602662, rs492602, rs681343, and rs281377) and BD was reported in Iranian and Turkish populations [126].

6.3 UBAC2

Ubiquitin-associated domain containing 2 (UBAC2) is another poorly characterized protein, but its gene variants are strongly associated with BD. Limited studies suggest that it may function in protein localization in the endoplasmic reticulum [127]. The association of the UBAC2 gene with BD was found in Turkish, Chinese, Italian, and Japanese populations [128, 129, 130, 131]. Functionally, the presence of BD-risk rs9517723 allele was correlated with an increased expression of the UBAC2 gene.

6.4 SUMO4

Small ubiquitin-like modifier 4 (SUMO4) is a member of the SUMO family that post-transcriptionally sumoylates the targeted proteins to regulate their subcellular localization and/or enhance their stability and activity [132]. It is involved in immune regulation by negatively controlling NFκB activity [133]. The genetic association between the SUMO4 (SNPs rs237024, rs237026) and BD was first reported in a Chinese cohort, and that appeared independent from HLA-B51 [134]. The association was replicated in Tunisian and Korean cohorts [135, 136], in which specific polymorphisms were also associated with disease severity, skin lesions, and vascular involvement of BD patients [135, 136].

6.5 LACC1

LACC1 encodes an oxidoreductase that promotes fatty-acid oxidation. It also functions in activation of inflammasome, bactericidal activity of macrophages, and production of mitochondrial and NADPH-oxidase-dependent reactive oxygen species [137]. SNP rs9316059 of the LACC1 was associated with BD in Turkish, Japanese, and Chinese cohorts [78, 138].

6.6 Loci at ADO-EGR2 and CEBPB-PTPN1

Two genetic loci between the ADO and the EGR2 genes and the CEBPB and the PTPN1 genes were associated with BD in the Turkish, Iranian, and Japanese cohorts [78]. The ADO encodes cysteamine (2-aminoethanethiol) dioxygenase that is involved in amino acid metabolism [139]. The EGR2 encodes early growth response protein 2 that is a transcription factor, and highly expressed in a population of migrating neural crest cells [140]. CEBPB encodes CCAAT/enhancer binding protein beta, a member of the CCAAT/enhancer binding protein family of basic leucine zipper transcription factors. It functions in controlling cell differentiation, proliferation, and inflammation [141]. The PTPN1 gene encodes protein tyrosine phosphatase, nonreceptor type 1 that functions as a key regulator of immune homeostasis by inhibiting T-cell receptor signaling and by selectively promoting type I interferon responses after activation of myeloid-cell pattern-recognition receptors [142].

It is worth noting that these BD-linked loci do not directly reflect the association of the corresponding genes, but may be suggestive for further investigation of these genes in terms of their genetic and functional importance to BD.


7. Conclusion

Multiple genes have been associated with BD, and many of them are involved in immune activation and regulation that may suggest their potential biological relevance to chronic inflammatory nature of BD. However, exact pathogenic mechanisms of BD on these genes are still unclear. Like many other immune-regulatory diseases, this multigenic feature of BD underlies complex pathogenesis. Some of the reported associations, for example, TNFAIP3 and TLR4, appeared to be conflict in different study cohorts and/or populations, which suggests that the BD-associated polymorphisms of the genes may be ethnic specific, or sample selection bias may have occurred and further verification may be warranted. In addition, some of the BD-associated genes, for example, HLA-B, ERAP1, MICA, and IL family, have also been reported in other immune-mediated diseases, which supports the shared genetic effects among these diseases. Moreover, specific gene polymorphisms were associated with clinical presentation of BD, for example, HLA-A02:07 with skin lesions and arthritis, HLA-A*26:01 with uveitis, HLA-A*30:04 with vascular lesions and genital ulcers, MICA-A5.1 with ocular lesions, and MICA-A9 with neurological and intestinal involvement. Thus, these specific genotypes may be further explored as potential biomarkers for diagnostic or prognostic classification of BD patients.

While the genetic studies have supported multigenic contribution to susceptibility to BD, epigenetic alternations including DNA methylation, histone modifications, and microRNAs regulation have also been reported in BD [143]. Furthermore, there is appealing evidence indicating environmental factors, especially that microorganisms may trigger the disease [144]. Understanding the genetics of BD in conjunction with epigenetics and environmental triggers of BD will provide insights into pathogenesis of the disease and an opportunity to interrogate candidate genes in potential diagnostic and therapeutic applications.


  1. 1. Saadoun D, Wechsler B. Behçet’s disease. Orphanet Journal of Rare Diseases. 2012;12(7):20
  2. 2. Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR. Behçet’s disease, the silk road and HLA-B51: Historical and geographical perspectives. Tissue Antigens. 1999;54:213-220
  3. 3. Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. HLA and non-HLA genes in Behçet’s disease: A multicentric study in the Spanish population: A population-based study. Arthritis and Rheumatism. 2009;61:600-604
  4. 4. Shahram F, Jamshidi AR, Hirbod-Mobarakeh A, Habibi G, Mardani A, Ghaemi M. Scientometric analysis and mapping of scientific articles on Behçet’s disease. International Journal of Rheumatic Diseases. 2013;16:185-192
  5. 5. Azizlerli G, Kose AA, Sarica R, Gul A, Tutkun IT, Kulac M, et al. Prevalence of Behçet’s disease in Istanbul. Turkey International Journal of Dermatology. 2003;42:803-806
  6. 6. Yurdakul S, Günaydin I, Tüzün Y, Tankurt N, Pazarli H, Ozyazgan Y, et al. The prevalence of Behçet’s syndrome in a rural area in northern Turkey. The Journal of Rheumatology. 1988;15:820-822
  7. 7. Idil A, Gurler A, Boyvat A, Caliskan D, Ozdemir O, Isik A, et al. The prevalence of Behçet’s disease above the age of 10 years. The results of a pilot study conducted at the Park primary health care center in Ankara, Turkey. Ophthalmic Epidemiology. 2002;9:325-331
  8. 8. Ozyurt K, Colgecen E, Baykan H. Does familial occurrence or family history of recurrent oral ulcers influence clinical characteristics of Behçet’s disease? Acta Dermatovenerologica Croatica. 2013;21(3):168-173
  9. 9. Davatchi F, Shahram F, Chams-Davatchi C, Sadeghi Abdollahi B, Shams H, Nadji A, et al. Behçet’s disease: Is there a gender influence on clinical manifestations? International Journal of Rheumatic Diseases. 2012;15:306-314
  10. 10. Ono S, Aoki K, Sugiura S, Nakayama E, Letter IK. HL-A5 and Behçet’s disease. Lancet. 1973;2:1383-1384
  11. 11. Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M. Close association of HLA-Bw51 with Behçet’s disease. Archives of Ophthalmology. 1982;100:1455-1458
  12. 12. Saadoun D, Wechsler B, Desseaux K, Le Thi Huong D, Amoura Z, Resche-Rigon M, et al. Mortality in Behçet’s disease. Arthritis and Rheumatism. 2010;62:2806-2812
  13. 13. Demirseren DD, Ceylan GG, Akoglu G, Emre S, Erten S, Arman A, et al. HLA-B51 subtypes in Turkish patients with Behçet’s disease and their correlation with clinical manifestations. Genetics and Molecular Research. 2014;13:4788-4796
  14. 14. Hamzaoui A, Houman MH, Massouadia M, Ben Salem T, Khanfir MS, Ben Ghorbel I, et al. Contribution of Hla-B51 in the susceptibility and specific clinical features of Behçet’s disease in Tunisian patients. European Journal of Internal Medicine. 2012;23(4):347-349
  15. 15. Salvarani C, Boiardi L, Mantovani V, Olivieri I, Ciancio G, Cantini F, et al. Association of MICA alleles and HLA-B51 in Italian patients with Behçet’s disease. Journal of Rheumatology. 2001;28:1867-1870
  16. 16. Kilmartin DJ, Finch A, Acheson RW. Primary association of HLA-B51 with Behçet’s disease in Ireland. British Journal of Ophthalmology. 1997;81:649-653
  17. 17. Lennikov A, Alekberova Z, Goloeva R, Kitaichi N, Denisov L, Namba K, et al. Single center study on ethnic and clinical features of Behçet’s disease in Moscow, Russia. Clinical Rheumatology. 2015;34:321-327
  18. 18. Paul M, Klein T, Krause I, Molad Y, Narinsky R, Weinberger A. Allelic distribution of HLA-B*5 in HLA-B5-positive Israeli patients with Behçet’s disease. Tissue Antigens. 2001;58:185-186
  19. 19. Mizuki N, Ota M, Katsuyama Y, Yabuki K, Ando H, Shiina T, 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;59:118-121
  20. 20. Koumantaki Y, Stavropoulos C, Spyropoulou M, Messini H, Papademetropoulos M, Giziaki E, et al. HLA-B5101 in Greek patients with Behçet’s disease. Human Immunology. 1998;59:250-255
  21. 21. Mizuki N, Ota M, Katsuyama Y, Yabuki K, Ando H, Yoshida M, et al. HLA class I genotyping including HLA-B*51 allele typing in the Iranian patients with Behçet’s disease. Tissue Antigens. 2001;57:457-462
  22. 22. Ortiz-Fernández L, Carmona FD, Montes-Cano MA, García-Lozano JR, Conde-Jaldón M, Ortego-Centeno N, 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
  23. 23. de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLA-B51/B5 and the risk of Behçet’s disease: A systematic review and meta-analysis of case-control genetic association studies. Arthritis and Rheumatism. 2009;61:1287-1296
  24. 24. Montes-Cano MA, Conde-Jaldón M, García-Lozano JR, et al. HLA and non-HLA genes in Behçet’s disease: A multicentric study in the Spanish population. Arthritis Research & Therapy. 2013;15:145
  25. 25. Takeuchi M, Kastner DL, Remmers EF. The immunogenetics of Behçet’s disease: A comprehensive review. Journal of Autoimmunity. 2015;64:137-148
  26. 26. Radouane A, Oudghiri M, Chakib A, Naya A, Belhouari A, El Malki A, et al. HLA-B*27 allele associated to Behçet’s disease and to anterior uveitis in Moroccan patients. Annales de Biologie Clinique. 2011;69:419-424
  27. 27. Al Mosawi ZS, Madan W, Fareed E. Pediatric-onset Behçet disease in Bahrain: Report of nine cases and literature review. Archives of Iranian Medicine. 2012;15(8):485-487
  28. 28. Meguro A, Inoko H, Ota M, Katsuyama Y, Oka A, Okada E, et al. Genetics of Behçet disease inside and outside the MHC. Annals of the Rheumatic Diseases. 2010;69:747-754
  29. 29. Al-Okaily F, Al-Rashidi S, Al-Balawi M, Mustafa M, Arfin M, Al-Asmari A. Genetic association of HLA-A*26, -A*31, and -B*51 with Behçet’s disease in Saudi patients. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders. 2016;9:167-173
  30. 30. Kaburaki T, Takamoto M, Numaga J, Kawashima H, Araie M, Ohnogi Y, et al. Genetic association of HLA-A*2601 with ocular Behçet’s disease in Japanese patients. Clinical and Experimental Rheumatology. 2010;28:S39-S44
  31. 31. Kang EH, Park JW, Park C, Yu HG, Lee EB, Park MH, et al. Genetic and non-genetic factors affecting the visual outcome of ocular Behçet’s disease. Human Immunology. 2013;74:1363-1367
  32. 32. Kang EH, Kim JY, Takeuchi F, Kim JW, Shin K, Lee EY, et al. Associations between the HLA-A polymorphism and the clinical manifestations of Behçet’s disease. Arthritis Research & Therapy. 2011;13:R49
  33. 33. Ting JP, Trowsdale J. Genetic control of MHC class II expression. Cell. 2002;109:S21-S33
  34. 34. Devaiah BN, Singer DS. CIITA and its dual roles in MHC gene transcription. Frontiers in Immunology. 2013;4:476-481
  35. 35. Li L, Yu H, Jiang Y, Deng B, Bai L, Kijlstra A, et al. Genetic variations of NLR family genes in Behçet’s disease. Scientific Reports. 2016;6:20098-20104
  36. 36. 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. Nature Genetics. 2013;45:202-207
  37. 37. Zhang L, Yu H, Zheng M, Li H, Liu Y, Kijlstra A, et al. Association of ERAP1 gene polymorphisms with Behçet’s disease in Han Chinese. Investigative Ophthalmology & Visual Science. 2015;56:6029-6035
  38. 38. Conde-Jaldón M, Montes-Cano MA, García-Lozano JR, Ortiz-Fernández L, Ortego-Centeno N, González-León R, et al. Epistatic interaction of ERAP1 and HLA-B in Behçet disease: A replication study in the Spanish population. PLoS One. 2014;9:e102100
  39. 39. Choy MK, Phipps ME. MICA polymorphism: Biology and importance in immunity and disease. Trends in Molecular Medicine. 2010;16:97-106
  40. 40. Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proceedings of the National Academy of Sciences of the United States of America. 1994;91:6259-6263
  41. 41. Zhou X, Wang J, Zou H, Ward MM, Weisman MH, Espitia MG, et al. MICA, a gene contributing strong susceptibility to ankylosing spondylitis. Annals of the Rheumatic Diseases. 2014;73:1552-1557
  42. 42. Muñoz-Saá I, Cambra A, Pallarés L, Espinosa G, Juan A, Pujalte F, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet’s disease. Scandinavian Journal of Immunology. 2006;64:77-82
  43. 43. Mizuki N, Ota M, Kimura M, Ohno S, Ando H, Katsuyama Y, et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: A strong association of six GCT repetitions with Behçet disease. Proceedings of the National Academy of Sciences of the United States of America. 1997;94:1298-1303
  44. 44. Wei F, Zhang YU, Li W. A meta-analysis of the association between Behçet’s disease and MICA-A6. Biomedical Reports. 2016;4:741-745
  45. 45. Park SH, Park KS, Seo YI, Min DJ, Kim WU, Kim TG, et al. Association of MICA polymorphism with HLA-B51 and disease severity in Korean patients with Behçet’s disease. Journal of Korean Medical Science. 2002;17:366-370
  46. 46. Zhang J, Liao D, Yang L, Hou S. Association between Functional MICA-TM and Behçet’s disease: A systematic review and meta-analysis. Scientific Reports. 2016;6:21033
  47. 47. Nishiyama M, Takahashi M, Kuriyama T, Nakae K. Research report: Frequencies of mica gene polymorphism: A comparison between Indonesians on Bacan Island and suburban Japanese. The Southeast Asian Journal of Tropical Medicine and Public Health. 2004;35:195-201
  48. 48. Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, Moore KW, et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. Journal of Immunology. 1991;146:3444-3451
  49. 49. Mosmann TR, Coffman RL. TH1 and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology. 1989;7:145-173
  50. 50. Wallace GR, Kondeatis E, Vaughan RW, et al. IL-10 genotype analysis in patients with Behçet’s disease. Human Immunology. 2007;68:122-127
  51. 51. Hu J, Hou S, Zhu X, Fang J, Zhou Y, Liu Y, et al. Interleukin-10 gene polymorphisms are associated with Behçet’s disease but not with Vogt-Koyanagi-Harada syndrome in the Chinese Han population. Molecular Vision. 2015;21:589-603
  52. 52. 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. Nature Genetics. 2010;42:698-702
  53. 53. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nature Genetics. 2010;42:703-706
  54. 54. Akdis M, Burgler S, Crameri R, et al. Interleukins, from 1 to 37, and interferon-γ: Receptors, functions, and roles in diseases. The Journal of Allergy and Clinical Immunology. 2011;127:701-721
  55. 55. Chang JT, Shevach EM, Segal BM. Regulation of interleukin (IL)-12 receptor beta2 subunit expression by endogenous IL-12: A critical step in the differentiation of pathogenic autoreactive T cells. The Journal of Experimental Medicine. 1999;189:969-978
  56. 56. Watford WT, Hissong BD, Bream JH, et al. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunological Reviews. 2004;202:139-156
  57. 57. 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
  58. 58. Murphy CA, Langrish CL, Chen Y, et al. Divergent pro-and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. The Journal of Experimental Medicine. 2003;198:1951-1957
  59. 59. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in inflammation. The Journal of Clinical Investigation. 2006;116:1218-1222
  60. 60. Steinman L. Mixed results with modulation of TH-17 cells in human autoimmune diseases. Nature Immunology. 2010;11:41-44
  61. 61. Kirino Y, Zhou Q , Ishigatsubo Y, Mizuki N, Tugal-Tutkun I, Seyahi E, et al. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:8134-8139
  62. 62. Yu H, Zheng M, Zhang L, Li H, Zhu Y, Cheng L, et al. Identification of susceptibility SNPs in IL10 and IL23R-IL12RB2 for Behçet’s disease in Han Chinese. The Journal of Allergy and Clinical Immunology. 2017;139:621-627
  63. 63. Qin X, Xu J, Wu Z, Sun F, Chen H, Zheng W, et al. Association study of rs924080 and rs11209032 polymorphisms of IL23R-IL12RB2 in a northern Chinese Han population with Behçet’s disease. Human Immunology. 2016;77:1284-1290
  64. 64. Xavier JM, Shahram F, Davatchi F, et al. Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behçet’s disease. Arthritis and Rheumatism. 2012;64:2761-2772
  65. 65. Khaib Dit Naib O, Aribi M, Idder A, Chiali A, Sairi H, Touitou I, et al. Association analysis of IL10, TNF-α, and IL23R-IL12RB2 SNPs with Behçet’s disease risk in Western Algeria. Frontiers in Immunology. 2013;4:342
  66. 66. Kang EH, Kim S, Park MY, Choi JY, Choi IA, Kim MJ, et al. Behçet’s disease risk association fine-mapped on the IL23R-IL12RB2 intergenic region in Koreans. Arthritis Research & Therapy. 2017;19:227
  67. 67. Mirchandani AS, Salmond RJ, Liew FY. Interleukin-33 and the function of innate lymphoid cells. Trends in Immunology. 2012;33(8):389-396
  68. 68. Talei M, Abdi A, Shanebandi D, Jadidi-Niaragh F, Khabazi A, Babaie F, et al. Interleukin-33 gene expression and rs1342326 polymorphism in Behçet’s disease. Immunology Letters. 2018;S0165-2478(17):30443-30441
  69. 69. Chae JJ, Wood G, Masters SL, Richard K, Park G, Smith BJ, et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:9982-9987
  70. 70. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nature Genetics. 1997;17:25-31
  71. 71. Touitou I, Magne X, Molinari N, Navarro A, Quellec AL, et al. MEFV mutations in Behçet’s disease. Human Mutation. 2000;16:271-272
  72. 72. Esmaeili M, Bonyadi M, Khabbazi A, Ebrahimi AA, Sharif SK, et al. Common MEFV mutations in Iranian Azeri Turkish patients with Behçet’s disease. Scandinavian Journal of Rheumatology. 2011;40:383-386
  73. 73. Wu Z, Zhang S, Li J, Chen S, Li P, Sun F, et al. Association between MEFV mutations M694V and M680I and Behçet’s disease: A meta-analysis. PLoS One. 2015;10:e0132704
  74. 74. Tasliyurt T, Yigit S, Rustemoglu A, Gul U, Ates O. Common MEFV gene mutations in Turkish patients with Behçet’s disease. Gene. 2013;530:100-103
  75. 75. Holtschke T, Lohler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell. 1996;87:307-317
  76. 76. Ouyang X, Zhang R, Yang J, Li Q , Qin L, Zhu C, et al. Transcription factor IRF8 directs a silencing programme for TH17 cell differentiation. Nature Communications. 2011;2:314
  77. 77. 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. Scientific Reports. 2016;6:19651
  78. 78. Takeuchi M, Mizuki N, Meguro A, Ombrello MJ, Kirino Y, Satorius C, et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility. Nature Genetics. 2017;49:438-443
  79. 79. Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, et al. The ubiquitin-modifying enzyme A20 is required for termination of toll-like receptor responses. Nature Immunology. 2004;5:1052-1060
  80. 80. Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE, et al. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity. 2008;28:381-390
  81. 81. Jaattela M, Mouritzen H, Elling F, Bastholm L. A20 zinc finger protein inhibits TNF and IL-1 signaling. Journal of Immunology. 1996;156:1166-1173
  82. 82. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science. 2000;289:2350-2354
  83. 83. Li H, Liu Q , Hou S, Du L, Zhou Q , Zhou Y, et al. TNFAIP3 gene polymorphisms confer risk for Behçet’s disease in a Chinese Han population. Human Genetics. 2013;132:293-300
  84. 84. Ortiz-Fernández L, García-Lozano JR, Montes-Cano MA, Conde-Jaldón M, Ortego-Centeno N, et al. Lack of association of TNFAIP3 and JAK1 with Behçet’s disease in the European population. Clinical and Experimental Rheumatology. 2015;33(6 Suppl 94):S36-S39
  85. 85. Shigemura T, Kaneko N, Kobayashi N, Kobayashi K, Takeuchi Y, Nakano N, et al. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet’s disease. RMD Open. 2016;2:e000223
  86. 86. Chen G, Hardy K, Pagler E, Ma L, Lee S, Gerondakis S, et al. The NF-κB transcription factor c-Rel is required for Th17 effector cell development in experimental autoimmune ncephalomyelitis. Journal of Immunology. 2011;187:4483-4491
  87. 87. Lamhamedi-Cherradi SE, Zheng S, Hilliard BA, Xu L, Sun J, Alsheadat S, et al. Transcriptional regulation of type I diabetes by NF-kappa B. Journal of Immunology. 2003;171:4886-4892
  88. 88. Chen F, Xu L, Zhao T, Xiao X, Pan Y, Hou S. Genetic variation in the REL gene increases risk of Behçet’s disease in a Chinese Han population but that of PRKCQ does not. PLoS One. 2016;11:147350
  89. 89. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in Tlr4 gene. Science. 1998;282:2085-2088
  90. 90. Fang J, Hu R, Hou S, Ye Z, Xiang Q , Qi J, et al. Association of TLR2 gene polymorphisms with ocular Behçet’s disease in a Chinese Han population. Investigative Ophthalmology & Visual Science. 2013;54:8384-8392
  91. 91. Meguro A, Ota M, Katsuyama Y, Oka A, Ohno S, Inoko H, et al. Association of the toll-like receptor 4 gene polymorphisms with Behçet’s disease. Annals of the Rheumatic Diseases. 2008;67:725-727
  92. 92. Horie Y, Meguro A, Ota M, Kitaichi N, Katsuyama Y, et al. Association of TLR4 polymorphisms with Behçet’s disease in a Korean population. Rheumatology. 2009;48:638-642
  93. 93. Boiardi L, Atzeni F, Casali B, Farnetti E, Nicoli D, et al. Toll-like receptor 4 (TLR4) gene polymorphisms in Italian patients with Behçet’s disease. Clinical and Experimental Rheumatology. 2009;27(Suppl 53):S43-S47
  94. 94. Ben Dhifallah I, Lachheb J, Houman H, Hamzaoui K. Toll-like-receptor gene polymorphisms in a Tunisian population with Behçet’s disease. Clinical and Experimental Rheumatology. 2009;27(Suppl 53):S58-S62
  95. 95. Du L, Yang P, Hou S, Zhou H, Kijlstra A. No association of CTLA-4 polymorphisms with susceptibility to Behçet disease. The British Journal of Ophthalmology. 2009;93:1378-1381
  96. 96. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nature Genetics. 2000;25:187-191
  97. 97. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nature Reviews Immunology. 2006;6:9-20
  98. 98. Moreira LO, Zamboni DS. NOD1 and NOD2 signaling in infection and inflammation. Frontiers in Immunology. 2012;3:328-334
  99. 99. Kappen JH, Wallace GR, Stolk L, Rivadeneira F, Uitterlinden AG, van Daele PL, et al. Low prevalence of NOD2 SNPs in Behçet’s disease suggests protective association in Caucasians. Rheumatology. 2009;48:1375-1377
  100. 100. Burillo-Sanz S, Montes-Cano MA, García-Lozano JR, Ortiz-Fernández L, Ortego-Centeno N. Mutational profile of rare variants in inflammasome-related genes in Behçet disease: A next generation sequencing approach. Scientific Reports. 2017;7:8453
  101. 101. Di Marzio P, Dai WW, Franchin G, Chan AY, Symons M, Sherry B. Role of rho family GTPases in CCR1- and CCR5-induced actin reorganization in macrophages. Biochemical and Biophysical Research Communications. 2005;331:909-916
  102. 102. 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. Human Genetics. 2012;131:1841-1850
  103. 103. Sousa I, Shahram F, Francisco D, Davatchi F, Abdollahi BS, Ghaderibarmi F, et al. Brief report: Association of CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 with Behçet’s disease in Iranians. Arthritis & Rhematology. 2015;67:2742-2748
  104. 104. Filén JJ, Filén S, Moulder R, Tuomela S, Ahlfors H, West A, et al. Quantitative proteomics reveals GIMAP family proteins 1 and 4 to be differentially regulated during human T helper cell differentiation. Molecular & Cellular Proteomics. 2009;8:32-44
  105. 105. Saunders A, Webb LM, Janas ML, Hutchings A, Pascall J, Carter C, et al. Putative GTPase GIMAP1 is critical for the development of mature B and T lymphocytes. Blood. 2010;115:3249-3257
  106. 106. Lee YJ, Horie Y, Wallace GR, Choi YS, Park JA, Choi JY, et al. Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behçet’s disease. Annals of the Rheumatic Diseases. 2013;72:1510-1516
  107. 107. Ortiz-Fernández L, Conde-Jaldón M, García-Lozano JR, Montes-Cano MA, Ortego-Centeno N, Castillo-Palma MJ, et al. GIMAP and Behçet disease: no association in the European population. Annals of the Rheumatic Diseases. 2014;73:1433-1454
  108. 108. Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proceedings of the National Academy of Sciences of the United States of America. 2002;99:12281-12286
  109. 109. Kim J, Park JA, Lee EY, Lee YJ, Song YW, Lee EB. Imbalance of Th17 to Th1 cells in Behçet’s disease. Clinical and Experimental Rheumatology. 2010;28:S16-S19
  110. 110. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q , O’Malley JT, et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. Journal of Immunology. 2007;178:4901-4907
  111. 111. Hou S, Yang Z, Du L, Jiang Z, Shu Q , Chen Y, et al. Identification of a susceptibility locus in STAT4 for Behçet’s disease in Han Chinese in a genome-wide association study. Arthritis and Rheumatism. 2012;64:4104-4113
  112. 112. Zervou MI, Goulielmos GN, Castro-Giner F, Boumpas DT, Tosca AD, Krueger-Krasagakis S. A CD40 and an NCOA5 gene polymorphism confer susceptibility to psoriasis in a southern European population: A case-control study. Human Immunology. 2011;72:761-765
  113. 113. Böser A, Drexler HC, Reuter H, Schmitz H, Wu G, Schöler HR, et al. SILAC proteomics of planarians identifies NCOA5 as a conserved component of pluripotent stem cells. Cell Reports. 2013;5:1142-1155
  114. 114. Rustemoglu A, Erkol Inal E, Inanir A, Ekinci D, Gul U, Yigit S, et al. Clinical significance of NCOA5 gene rs2903908 polymorphism in Behçet’s disease. EXCLI Journal. 2017;16:609-617
  115. 115. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22(3):329-341
  116. 116. Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 2007;445(7130):931-935
  117. 117. Hosseini A, Shanehbandi D, Estiar MA, Gholizadeh S, Khabbazi A, Khodadadi H, et al. A single nucleotide polymorphism in the FOXP3 gene associated with Behçet’s disease in an Iranian population. Clinical Laboratory. 2015;61(12):1897-1903
  118. 118. Liao D, Hou S, Zhang J, Fang J, Liu Y, Bai L, et al. Copy number variants and genetic polymorphisms in TBX21, GATA3, Rorc, Foxp3 and susceptibility to Behçet’s disease and Vogt-Koyanagi-Harada syndrome. Scientific Reports. 2015;5:9511
  119. 119. Holm SJ, Carlén LM, Mallbris L, Ståhle-Bäckdahl M, O’Brien KP. Polymorphisms in the SEEK1 and SPR1 genes on 6p21.3 associate with psoriasis in the Swedish population. Experimental Dermatology. 2003;12:435-444
  120. 120. Rahman P, Butt C, Siannis F, Farewell VT, Peddle L, Pellett FJ, et al. Association of SEEK1 and psoriatic arthritis in two distinct Canadian populations. Annals of the Rheumatic Diseases. 2005;64:1370-1372
  121. 121. Bossini-Castillo L, Martin JE, Broen J, Simeon CP, Beretta L, Gorlova OY, et al. Confirmation of TNIP1 but not RHOB and PSORS1C1 as systemic sclerosis risk factors in a large independent replication study. Annals of the Rheumatic Diseases. 2013;72:602-607
  122. 122. Peddle L, Zipperlen K, Melay B, Hefferton D, Rahman P. Association of SEEK1 polymorphisms in Crohn’s disease. Human Immunology. 2004;65:706-709
  123. 123. Fan X, Yang S, Huang W, Wang ZM, Sun LD, Liang YH, et al. Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population. PLoS Genetics. 2008;4:e1000038
  124. 124. Reich K, Hüffmeier U, König IR, Lascorz J, Lohmann J, Wendler J, et al. TNF polymorphisms in psoriasis: Association of psoriatic arthritis with the promoter polymorphism TNF*-857 independent of the PSORS1 risk allele. Arthritis and Rheumatism. 2007;56:2056-2064
  125. 125. Ferrer-Admetlla A, Sikora M, Laayouni H, Esteve A, Roubinet F, Blancher A, et al. A natural history of FUT2 polymorphism in humans. Molecular Biology and Evolution. 2009;26:1993-2003
  126. 126. Xavier JM, Shahram F, Sousa I, Davatchi F, Matos M, Abdollahi BS, et al. FUT2: Filling the gap between genes and environment in Behçet’s disease? Annals of the Rheumatic Diseases. 2015;74:618-624
  127. 127. Olzmann JA, Richter CM, Kopito RR. Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:1345-1350
  128. 128. 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 Research & Therapy. 2009;11:R66
  129. 129. Sawalha AH, Hughes T, Nadig A, Yılmaz V, Aksu K, Keser G, et al. A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet’s disease. Arthritis and Rheumatism. 2011;63:3607-3612
  130. 130. 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 Research & Therapy. 2012;14:R70
  131. 131. 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. Scientific Reports. 2017;7:742-747
  132. 132. Rallabhandi P, Hashimoto K, Mo YY, Beck WT, Moitra PK, D’Arpa P. Sumoylation of topoisomerase I is involved in its partitioning between nucleoli and nucleoplasm and its clearing from nucleoli in response to camptothecin. The Journal of Biological Chemistry. 2002;277:40020-40026
  133. 133. Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, et al. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. Nature Genetics. 2004;36:837-841
  134. 134. Hou S, Yang P, Du L, Zhou H, Lin X, Liu X, et al. SUMO4 gene polymorphisms in Chinese Han patients with Behçet’s disease. Clinical Immunology. 2008;129:170-175
  135. 135. Kamoun M, Ben Dhifallah I, Karray E, Zakraoui L, Hamzaoui K. Association of small ubiquitin-like modifier 4 (SUMO4) polymorphisms in a Tunisian population with Behçet’s disease. Clinical and Experimental Rheumatology. 2010;28(Suppl. 60):S45-S49
  136. 136. Park G, Kim HS, Choe JY, Kim SK. SUMO4 C438T polymorphism is associated with papulopustular skin lesion in Korean patients with Behçet’s disease. Rheumatology International. 2012;32:3031-3037
  137. 137. Cader MZ, Boroviak K, Zhang Q , Assadi G, Kempster SL, Sewell GW, et al. C13orf31 (FAMIN) is a central regulator of immunometabolic function. Nature Immunology. 2016;17:1046-1056
  138. 138. Wu P, Du L, Hou S, Su G, Yang L, Hu J, et al. Association of LACC1, CEBPB-PTPN1, RIPK2 and ADO-EGR2 with ocular Behçet’s disease in a Chinese Han population. The British Journal of Ophthalmology. 2018;102:1308-1314
  139. 139. Sarkar B, Kulharia M, Mantha AK. Understanding human thiol dioxygenase enzymes: Structure to function, and biology to pathology. International Journal of Experimental Pathology. 2017;98:52-66
  140. 140. Wilkinson DG, Bhatt S, Chavrier P, et al. Segment-specific expression of a zinc-finger gene in the developing nervous system of the mouse. Nature. 1989;337(6206):461-464
  141. 141. Nerlov C. The C/EBP family of transcription factors: A paradigm for interaction between gene expression and proliferation control. Trends in Cell Biology. 2007;17:318-324
  142. 142. Sanford SM, Bottini N. PTPN22: The archetypal non-HLA autoimmunity gene. Nature Reviews Rheumatology. 2014;10:602-611
  143. 143. Alipour S, Nouri M, Sakhinia E, Samadi N, Roshanravan N, Ghavami A, et al. Epigenetic alterations in chronic disease focusing on Behçet’s disease: Review. Biomedicine & Pharmacotherapy. 2017;91:526-533
  144. 144. Hatemi G, Yazici H. Behçet’s syndrome and micro-organisms. Best Practice & Research. Clinical Rheumatology. 2011;25:389-406

Written By

Xiaodong Zhou and Yan Deng

Submitted: February 19th, 2019 Reviewed: May 27th, 2019 Published: August 30th, 2019