Beh？et's disease (BD) is a systemic inflammatory disorder characterized mainly by recurrent oral and genital ulcers and eye involvement. Although the pathogenesis remains poorly understood, a variety of studies have demonstrated that genetic predisposition is a major factor in disease susceptibility. Peculiar geographical distribution of BD along the ancient Silk Road has been regarded as evidence supporting genetic influence. The observed aggregation of BD in families of patients with BD is also supportive for a genetic component in its etiology. HLA-B51 (B510101 subtype) is the most strongly associated genetic marker for BD in countries on the Silk Road. In recent years, several genome-wide association studies and genetic polymorphism studies have also found new genetic associations with BD, which may have a supplementary role in disease susceptibility and/or severity. The author reviewed the HLA and non-HLA genetic association studies. 1. Introduction Beh？et’s disease (BD) is a complex syndrome characterized mainly by recurrent oral aphthous ulcers, genital ulcerations, and ocular involvement. This triple-symptom complex was first described by Hulusi Beh？et, a Turkish dermatologist, as a separate disease entity. Later, other associated clinical features were described [1, 2]. Although the aetiology is still obscure, BD is believed to be triggered by environmental factors such as microbial agents in individuals with a particular genetic background. Interactions of genetic and environmental factors in BD patients may underlie pathogenic processes, which may influence the development of the disease and modify its course. The prevalent distribution in a specific geographical area, the close association with HLA-B51 in different ethnic groups, and the familial clustering of BD are hallmarks accounting for the strong contribution of a genetic background [2, 3]. Here we review the current knowledge of the genetic basis of BD and their implications in pathogenesis of BD and summarize the important findings in Table 1. Table 1: Findings supporting the genetic background of Beh？et’s disease. 2. Geographical Distribution The prevalence of BD is known to be high in Japan, China, Turkey, and the Mediterranean and the Middle Eastern countries. It is hypothesized that this geographical distribution of BD from Japan to the Middle East and the Mediterranean basin correlates with the distribution of HLA-B51 by old nomadic or Turkish tribes via the ancient Silk Road. This peculiar geographical distribution have been regarded as evidence supporting genetic influence on
References
[1]
T. I. Kaya, H. Dur, U. Tursen, and A. Gurler, “Association of class I HLA antigens with the clinical manifestations of Turkish patients with Beh？et's disease,” Clinical and Experimental Dermatology, vol. 27, no. 6, pp. 498–501, 2002.
[2]
H. Beh？et, “Uber rezidiverende, apthose durch ein virus verursachte geschwure am mund, am auge und an der genitalen,” Dermatologische Wochenschrift, vol. 105, pp. 1152–1157, 1937.
[3]
P. Fietta, “Beh？et's disease: familial clustering and immunogenetics,” Clinical and Experimental Rheumatology, vol. 23, no. 4, supplement 38, pp. S96–S105, 2005.
[4]
S. Ohno, M. Onguchi, and S. Hirose, “Close association of HLA-Bw51 with Behcet's disease,” Archives of Ophthalmology, vol. 100, no. 9, pp. 1455–1458, 1982.
[5]
D. Mendes, M. Correia, M. Barbedo et al., “Beh？et's disease—a contemporary review,” Journal of Autoimmunity, vol. 32, no. 3-4, pp. 178–188, 2009.
[6]
G. Azizlerli, A. A. K？se, R. Sarica et al., “Prevalence of Beh？et's disease in Istanbul, Turkey,” International Journal of Dermatology, vol. 42, no. 10, pp. 803–806, 2003.
[7]
S. Yurdakul, I. Gunaydin, Y. Tuzun et al., “The prevalence of Behcet's syndrome in a rural area in northern Turkey,” Journal of Rheumatology, vol. 15, no. 5, pp. 820–822, 1988.
[8]
A. Idil, A. Gürler, A. Boyvat et al., “The prevalence of Beh？et'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, vol. 9, no. 5, pp. 325–331, 2002.
[9]
M. Piga and A. Mathieu, “Genetic susceptibility to Beh？et's disease: role of genes belonging to the MHC region,” Rheumatology, vol. 50, no. 2, pp. 299–310, 2011.
[10]
K. T. Calamia, F. C. Wilson, M. Icen, C. S. Crowson, S. E. Gabriel, and H. M. Kremers, “Epidemiology and clinical characteristics of behcet's disease in the us: a population-based study,” Arthritis Care and Research, vol. 61, no. 5, pp. 600–604, 2009.
[11]
C. C. Zouboulis, I. K？tter, D. Djawari et al., “Epidemiological Features of Adamantiades-Beh？et's Disease in Germany and in Europe,” Yonsei Medical Journal, vol. 38, no. 6, pp. 411–422, 1997.
[12]
N. G. Papoutsis, M. B. Abdel-Naser, A. Altenburg et al., “Prevalence of Adamantiades-Beh？et's disease in Germany and the municipality of Berlin: results of a nationwide survey,” Clinical and Experimental Rheumatology, vol. 24, no. 5, p. S125, 2006.
[13]
A. Gl, A. H. Hajeer, J. Worthington, J. H. Barrett, W. E. R. Ollier, and A. J. Silman, “Evidence for linkage of the HLA-B locus in Beh？et's disease, obtained using the transmission disequilibrium test,” Arthritis and Rheumatism, vol. 44, no. 1, pp. 239–240, 2001.
[14]
M. De Menthon, M. P. LaValley, C. Maldini, L. Guillevin, and A. Mahr, “HLA-B51/B5 and the risk of Beh？et's disease: a systematic review and meta-analysis of case-control genetic association studies,” Arthritis Care and Research, vol. 61, no. 10, pp. 1287–1296, 2009.
[15]
Y. Takemoto, T. Naruse, K. Namba et al., “Re-evaluation of heterogeneity in HLA-B510101 associated with Beh？et's disease,” Tissue Antigens, vol. 72, no. 4, pp. 347–353, 2008.
[16]
D. Middleton, L. Menchaca, H. Rood, and R. Komerofsky, “New allele frequency database: http://www.allelefrequencies.net/,” Tissue Antigens, vol. 61, no. 5, pp. 403–407, 2003.
[17]
C. Zouboulis, P. Buttner, D. Djawari, et al., “HLA-Class I antigens in German patients with Adamantiades-Beh？et’s disease and correlation with clinical manifestations,” in Beh？et’s Disease, P. Godeau and B. Wechsler, Eds., pp. 175–180, Elsevier, Amsterdam, The Netherlands, 1993.
[18]
Z. S. Alekberova, V. I. Madanat, I. S. Polianskaia, and T. B. Prokaeva, “The HLA-B5 immunogenetic marker in Beh？et's disease,” Terapevticheskii Arkhiv, vol. 65, no. 5, pp. 12–14, 1993.
[19]
A. U. Muftuoglu, H. Yazici, and S. Yurdakul, “Behcet's disease: Lack of correlation of clinical manifestations with HLA antigens,” Tissue Antigens, vol. 17, no. 2, pp. 226–230, 1981.
[20]
M. Takeno, A. Kariyone, N. Yamashita et al., “Excessive function of peripheral blood neutrophils from patients with Behcet's disease and from HLA-B51 transgenic mice,” Arthritis and Rheumatism, vol. 38, no. 3, pp. 426–433, 1995.
[21]
H. Yasuoka, Y. Okazaki, Y. Kawakami et al., “Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Beh？et's disease,” Arthritis and Rheumatism, vol. 50, no. 11, pp. 3658–3662, 2004.
[22]
A. Sensi, R. Gavioli, S. Spisani et al., “HLA B51 antigen associated with neutrophil hyper-reactivity,” Disease Markers, vol. 9, no. 6, pp. 327–331, 1991.
[23]
N. Mizuki, S. Ohno, H. Ando et al., “A strong association between HLA-B()5101 and Behcet's disease in Greek patients,” Tissue Antigens, vol. 50, no. 1, pp. 57–60, 1997.
[24]
I. Pirim, M. Atasoy, M. Ikbal, T. Erdem, and C. Aliagaoglu, “HLA class I and class II genotyping in patients with Behcet's disease: a regional study of eastern part of Turkey,” Tissue Antigens, vol. 64, no. 3, pp. 293–297, 2004.
[25]
K. S. Park, J. S. Park, J. H. Nam, D. Bang, S. Sohn, and E. S. Lee, “HLA-E0101 and HLA-G010101 reduce the risk of Behcet's disease,” Tissue Antigens, vol. 69, no. 2, pp. 139–144, 2007.
[26]
N. Mizuki, M. Ota, Y. Katsuyama et al., “Association analysis between the MIC-A and HLA-B alleles in Japanese patients with Behcet's disease,” Arthritis and Rheumatism, vol. 42, no. 9, pp. 1961–1966, 1999.
[27]
Y. Fei, R. Webb, B. L. Cobb, H. Direskeneli, G. Saruhan-Direskeneli, and A. H. Sawalha, “Identification of novel genetic susceptibility loci for Beh？et's disease using a genome-wide association study,” Arthritis Research and Therapy, vol. 11, no. 3, article R66, 2009.
[28]
E. F. Remmers, F. Cosan, Y. Kirino et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Beh？et's disease,” Nature Genetics, vol. 42, no. 8, pp. 698–702, 2010.
[29]
N. Mizuki, A. Meguro, M. Ota et al., “Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Beh？et's disease susceptibility loci,” Nature Genetics, vol. 42, no. 8, pp. 703–706, 2010.
[30]
A. Meguro, H. Inoko, M. Ota et al., “Genetics of Beh？et disease inside and outside the MHC,” Annals of the Rheumatic Diseases, vol. 69, no. 4, pp. 747–754, 2010.
[31]
J. Karasneh, A. Gül, W. E. Ollier, A. J. Silman, and J. Worthington, “Whole-genome screening for susceptibility genes in multicase families with Beh？et's disease,” Arthritis and Rheumatism, vol. 52, no. 6, pp. 1836–1842, 2005.
[32]
C. C. Zouboulis, “Epidemiology of Adamantiades-Behcet's disease,” Annales de Medecine Interne, vol. 150, no. 6, pp. 488–498, 1999.
[33]
T. Akpolat, Y. Ko？, I. Yeniay et al., “Familial Beh？et's disease,” The European journal of medicine, vol. 1, no. 7, pp. 391–395, 1992.
[34]
J. L. Villanueva, J. Gonzalez-Dominguez, R. Gonzalez-Fernandez, J. L. Prada, J. Pena, and R. Solana, “HLA antigen familial study in complete Behcet's syndrome affecting three sisters,” Annals of the Rheumatic Diseases, vol. 52, no. 2, pp. 155–157, 1993.
[35]
S. Bird and J. A. Stewart, “Genetic analysis of families of patients with Behcet's syndrome: data incompatible with autosomal recessive inheritance,” Annals of the Rheumatic Diseases, vol. 45, no. 4, pp. 265–268, 1986.
[36]
N. Molinari, I. Koné Paut, R. Manna, J. Demaille, J. P. Daures, and I. Touitou, “Identification of an autosomal recessive mode of inheritance in paediatric Beh？et's families by segregation analysis,” American Journal of Medical Genetics, vol. 122, no. 2, pp. 115–118, 2003.
[37]
I. Fresko, M. Soy, V. Hamuryudan et al., “Genetic anticipation in Behcet's syndrome,” Annals of the Rheumatic Diseases, vol. 57, no. 1, pp. 45–48, 1998.
[38]
R. Treudler, C. E. Orfanos, and C. C. Zouboulis, “Twenty-eight cases of juvenile-onset Adamantiades-Behcet disease in Germany,” Dermatology, vol. 199, no. 1, pp. 15–19, 1999.
[39]
M. Laghmari, A. Karim, F. Allali et al., “Childhood Beh？et's disease: clinical and evolutive aspects. About 13 cases,” Journal Francais d'Ophtalmologie, vol. 25, no. 9, pp. 904–908, 2002.
[40]
I. Koné-Paut, I. Geisler, B. Wechsler et al., “Familial aggregation in Behcet's disease: high frequency in siblings and parents of pediatric probands,” Journal of Pediatrics, vol. 135, no. 1, pp. 89–93, 1999.
[41]
A. Gül, M. Inanc, L. Ocal, O. Aral, and M. Konice, “Familial aggregation of Behcet's disease in Turkey,” Annals of the Rheumatic Diseases, vol. 59, no. 8, pp. 622–625, 2000.
[42]
A. Gül, F. A. Uyar, M. Inanc et al., “Lack of association of HLA-B*51 with a severe disease course in Beh？et's disease,” Rheumatology, vol. 40, no. 6, pp. 668–672, 2001.
[43]
S. Masatlioglu, E. Seyahi, E. Tahir Turanli et al., “A twin study in Beh？et's syndrome,” Clinical and Experimental Rheumatology, vol. 28, no. 4, supplement 60, pp. S62–S66, 2010.
[44]
T. Kobayashi, Y. Sudo, S. Okamura et al., “Monozygotic twins concordant for intestinal Beh？et's disease,” Journal of gastroenterology, vol. 40, no. 4, pp. 421–425, 2005.
[45]
V. Hamuryudan, S. Yurdakul, F. Ozbakir, H. Yazici, and H. Hekim, “Monozygotic twins concordant for Behcet's syndrome,” Arthritis and Rheumatism, vol. 34, no. 8, pp. 1071–1072, 1991.
[46]
A. Gül, M. Inanc, L. Ocal, O. Aral, M. Carin, and M. Konice, “HLA-B51 negative monozygotic twins discordant for Behcet's Disease,” British Journal of Rheumatology, vol. 36, no. 8, pp. 922–923, 1997.
[47]
S. Yilmaz and K. A. Cimen, “Familial Beh？et's disease,” Rheumatology International, vol. 30, no. 8, pp. 1107–1109, 2010.
[48]
U. Tursen, L. Tamer, G. Eskandari et al., “Glutathione S-transferase polymorphisms in patients with Beh？et's disease,” Archives of Dermatological Research, vol. 296, no. 4, pp. 185–187, 2004.
[49]
I. Krause and A. Weinberger, “Beh？et's disease,” Current Opinion in Rheumatology, vol. 20, no. 1, pp. 82–87, 2008.
[50]
H. Yanagihori, N. Oyama, K. Nakamura, N. Mizuki, K. Oguma, and F. Kaneko, “Role of IL-12B promoter polymorphism in Adamantiades-Behcet's disease susceptibility: an involvement of Th1 immunoreactivity against Streptococcus sanguinis antigen,” Journal of Investigative Dermatology, vol. 126, no. 7, pp. 1534–1540, 2006.
[51]
W. C. Jang, Y. H. Nam, Y. C. Ahn et al., “Interleukin-17F gene polymorphisms in Korean patients with Beh？et's disease,” Rheumatology International, vol. 29, no. 2, pp. 173–178, 2008.
[52]
Z. Jiang, P. Yang, S. Hou et al., “IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population,” Annals of the Rheumatic Diseases, vol. 69, no. 7, pp. 1325–1328, 2010.
[53]
G. Polat, G. Eskandari, T. I. Kaya et al., “Association of the platelet glycoprotein Ia C807T/G873A gene polymorphism and thrombosis in beh？et patients,” Haematologia, vol. 32, no. 2, pp. 121–128, 2002.
[54]
A. Gül, U. ？zbek, C. ？ztürk, M. Inan？, M. Koni？e, and T. ？zcelik, “Coagulation factor V gene mutation increases the risk of venous thrombosis in Behcet's disease,” British Journal of Rheumatology, vol. 35, no. 11, pp. 1178–1180, 1996.
[55]
C. Salvarani, K. Calamia, M. Silingardi, A. Ghirarduzzi, and I. Olivieri, “Thrombosis associated with the prothrombin G→A20210 mutation in Behcet's disease,” Journal of Rheumatology, vol. 27, no. 2, pp. 515–516, 2000.
[56]
U. Tursen, T. I. Kaya, G. Eskandari et al., “Association of factor V Leiden and prothrombin gene mutation with Beh？et's disease,” Archives of Dermatological Research, vol. 293, no. 10, pp. 537–539, 2001.
