Purpose To investigate the associations of single nucleotide polymorphisms (SNPs) of three genes (IL-12B, IL-12Rβ1 and IL-12Rβ2) in Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in a Chinese Han population. Methods A total of 806 BD cases, 820 VKH patients, and 1600 healthy controls were involved in this study. The first investigation included 400 BD patients, 400 VKH cases, and 600 healthy individuals. A second confirmatory study included a separate set of 406 BD patients, 420 VKH cases and another 1000 normal controls. Genotyping was carried out by PCR-restriction fragment length polymorphism assay and results were validated by using direct sequencing. The χ2 test was performed to compare the allele and genotype frequencies between cases and healthy controls. Results This study comprised two phases. In the first phase study, a significantly increased frequency of the rs3212227/IL-12B genotype CC and C allele was found in BD patients as compared to controls (Bonferroni corrected p value (pc) = 0.009, OR 1.8; pc = 0.024, OR 1.3, respectively). Moreover, the frequency of the C allele of rs3212227/IL-12B was also significantly increased in VKH patients (pc = 0.012, OR 1.3, 95% CI 1.1 to 1.6). No associations were found for the other seven tested SNPs either in BD or VKH disease. The second study as well as the combined data confirmed the significant association of rs3212227/IL-12B with BD (CC genotype: combined pc = 6.3×10？7, OR = 1.8; C allele: combined pc = 2.0×10？5, OR = 1.3, respectively) and the C allele frequency of rs3212227/IL-12B as the risk factor to VKH patients (combined pc = 2.5×10？5, OR 1.3, 95% CI 1.2 to 1.5). Conclusions Our study revealed that the IL-12B gene is involved both in the susceptibility to BD as well as VKH syndrome.
References
[1]
Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behcet's disease. N Engl J Med 341: 1284–1291. doi: 10.1056/nejm199910213411707
[2]
Bang D, Hur W, Lee ES, Lee S (1995) Prognosis and clinical relevance of recurrent oral ulceration in Behcet's disease. J Dermatol 22: 926–929.
[3]
Alpsoy E, Zouboulis CC, Ehrlich GE (2007) Mucocutaneous lesions of Behcet's disease. Yonsei Med J 48: 573–585. doi: 10.3349/ymj.2007.48.4.573
[4]
Alpsoy E, Donmez L, Bacanli A, Apaydin C, Butun B (2003) Review of the chronology of clinical manifestations in 60 patients with Behcet's disease. Dermatology 207: 354–356. doi: 10.1159/000074113
[5]
Bank I, Duvdevani M, Livneh A (2003) Expansion of gammadelta T-cells in Behcet's disease: role of disease activity and microbial flora in oral ulcers. J Lab Clin Med 141: 33–40. doi: 10.1067/mlc.2003.1
[6]
Kulaber A, Tugal-Tutkun I, Yentur SP, Akman-Demir G, Kaneko F, et al. (2007) Pro-inflammatory cellular immune response in Behcet's disease. Rheumatol Int 27: 1113–1118. doi: 10.1007/s00296-007-0367-9
[7]
Chi W, Zhu X, Yang P, Liu X, Lin X, et al. (2008) Upregulated IL-23 and IL-17 in Behcet patients with active uveitis. Invest Ophthalmol Vis Sci 49: 3058–3064. doi: 10.1167/iovs.07-1390
[8]
Yang P, Ren Y, Li B, Fang W, Meng Q, et al. (2007) Clinical characteristics of Vogt-Koyanagi-Harada syndrome in Chinese patients. Ophthalmology 114: 606–614. doi: 10.1016/j.ophtha.2006.07.040
[9]
Murthy SI, Moreker MR, Sangwan VS, Khanna RC, Tejwani S (2007) The spectrum of Vogt-Koyanagi-Harada disease in South India. Int Ophthalmol 27: 131–136. doi: 10.1007/s10792-007-9046-9
[10]
Chi W, Yang P, Li B, Wu C, Jin H, et al. (2007) IL-23 promotes CD4+ T cells to produce IL-17 in Vogt-Koyanagi-Harada disease. J Allergy Clin Immunol 119: 1218–1224. doi: 10.1016/j.jaci.2007.01.010
[11]
Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR (1999) Behcet's disease, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens 54: 213–220. doi: 10.1034/j.1399-0039.1999.540301.x
[12]
Jiang Z, Yang P, Hou S, Du L, Xie L, et al. (2010) IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population. Ann Rheum Dis 69: 1325–1328. doi: 10.1136/ard.2009.119420
[13]
Fang J, Hou S, Xiang Q, Qi J, Yu H, et al.. (2014) Polymorphisms in genetics of vitamin d metabolism confer susceptibility to ocular behcet disease in a chinese han population. Am J Ophthalmol 157: : 488–494 e486.
[14]
Fang J, Hu R, Hou S, Ye Z, Xiang Q, et al. (2013) Association of TLR2 Gene Polymorphisms With Ocular Behcet's Disease in a Chinese Han Population. Invest Ophthalmol Vis Sci 54: 8384–8392. doi: 10.1167/iovs.13-12878
[15]
Zhao M, Jiang Y, Abrahams IW (1991) Association of HLA antigens with Vogt-Koyanagi-Harada syndrome in a Han Chinese population. Arch Ophthalmol 109: 368–370. doi: 10.1001/archopht.1991.01080030070041
[16]
Shu Q, Yang P, Hou S, Li F, Chen Y, et al. (2010) Interleukin-17 gene polymorphism is associated with Vogt-Koyanagi-Harada syndrome but not with Behcet's disease in a Chinese Han population. Hum Immunol 71: 988–991. doi: 10.1016/j.humimm.2010.06.020
[17]
Hu K, Yang P, Jiang Z, Hou S, Du L, et al. (2010) STAT4 polymorphism in a Chinese Han population with Vogt-Koyanagi-Harada syndrome and Behcet's disease. Hum Immunol 71: 723–726. doi: 10.1016/j.humimm.2010.04.007
[18]
Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol 3: 133–146. doi: 10.1038/nri1001
[19]
Trinchieri G, Pflanz S, Kastelein RA (2003) The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19: 641–644. doi: 10.1016/s1074-7613(03)00296-6
[20]
Khader SA, Partida-Sanchez S, Bell G, Jelley-Gibbs DM, Swain S, et al. (2006) Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J Exp Med 203: 1805–1815. doi: 10.1084/jem.20052545
[21]
Johnston A, Xing X, Swindell WR, Kochkodan J, Riblett M, et al. (2013) Susceptibility-associated genetic variation at IL12B enhances Th1 polarization in psoriasis. Hum Mol Genet 22: 1807–1815. doi: 10.1093/hmg/ddt034
[22]
Lim HX, Hong HJ, Jung MY, Cho D, Kim TS (2013) Principal role of IL-12p40 in the decreased Th1 and Th17 responses driven by dendritic cells of mice lacking IL-12 and IL-18. Cytokine 63: 179–186. doi: 10.1016/j.cyto.2013.04.029
[23]
Morahan G, Huang D, Ymer SI, Cancilla MR, Stephen K, et al. (2001) Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nat Genet 27: 218–221.
[24]
Wong RH, Wei JC, Huang CH, Lee HS, Chiou SY, et al. (2012) Association of IL-12B genetic polymorphism with the susceptibility and disease severity of ankylosing spondylitis. J Rheumatol 39: 135–140. doi: 10.3899/jrheum.110613
[25]
Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80: 273–290. doi: 10.1086/511051
[26]
Cleary AM, Tu W, Enright A, Giffon T, Dewaal-Malefyt R, et al. (2003) Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency. J Immunol 170: 597–603. doi: 10.4049/jimmunol.170.1.597
[27]
de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, et al. (2008) Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med 205: 1543–1550. doi: 10.1084/jem.20080321
[28]
Zhang GX, Yu S, Gran B, Li J, Siglienti I, et al. (2003) Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis. J Immunol 171: 4485–4492. doi: 10.4049/jimmunol.171.9.4485
[29]
van de Vosse E, Haverkamp MH, Ramirez-Alejo N, Martinez-Gallo M, Blancas-Galicia L, et al. (2013) IL-12Rbeta1 deficiency: mutation update and description of the IL12RB1 variation database. Hum Mutat 34: 1329–1339. doi: 10.1002/humu.22380
[30]
Szabo SJ, Dighe AS, Gubler U, Murphy KM (1997) Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells. J Exp Med 185: 817–824. doi: 10.1084/jem.185.5.817
[31]
Toh ML, Kawashima M, Hot A, Miossec P (2010) Role of IL-17 in the Th1 systemic defects in rheumatoid arthritis through selective IL-12Rbeta2 inhibition. Ann Rheum Dis 69: 1562–1567. doi: 10.1136/ard.2009.111757
[32]
Fauconnier M, Palomo J, Bourigault ML, Meme S, Szeremeta F, et al. (2012) IL-12Rbeta2 is essential for the development of experimental cerebral malaria. J Immunol 188: 1905–1914. doi: 10.4049/jimmunol.1101978
[33]
International Study Group for Behcet's Disease (1990) Criteria for diagnosis of Behcet's disease. Lancet 335: 1078–1080. doi: 10.1016/0140-6736(90)92643-v
[34]
Read RW, Holland GN, Rao NA, Tabbara KF, Ohno S, et al. (2001) Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol 131: 647–652. doi: 10.1016/s0002-9394(01)00925-4
[35]
Guenane H, Hartani D, Chachoua L, Lahlou-Boukoffa OS, Mazari F, et al. (2006) [Production of Th1/Th2 cytokines and nitric oxide in Behcet's uveitis and idiopathic uveitis]. J Fr Ophtalmol 29: 146–152. doi: 10.1016/s0181-5512(06)73762-7
[36]
Na SY, Park MJ, Park S, Lee ES (2013) Up-regulation of Th17 and related cytokines in Behcet's disease corresponding to disease activity. Clin Exp Rheumatol 31: 32–40.
[37]
Alayli G, Aydin F, Coban AY, Sullu Y, Canturk F, et al. (2007) T helper 1 type cytokines polymorphisms: association with susceptibility to Behcet's disease. Clin Rheumatol 26: 1299–1305. doi: 10.1007/s10067-006-0503-z
[38]
Yanagihori H, Tojo M, Inoue T, Nakamura K, Kaneko F, et al. (2004) Lack of association of interleukin-12 p40 gene (IL12B) polymorphism with Behcet's disease in the Japanese population. J Dermatol Sci 34: 112–114. doi: 10.1016/j.jdermsci.2003.12.004
[39]
Kaarvatn MH, Vrbanec J, Kulic A, Knezevic J, Petricevic B, et al. (2012) Single nucleotide polymorphism in the interleukin 12B gene is associated with risk for breast cancer development. Scand J Immunol 76: 329–335. doi: 10.1111/j.1365-3083.2012.02736.x
[40]
Oka A, Mabuchi T, Ikeda S, Terui T, Haida Y, et al. (2013) IL12B and IL23R gene SNPs in Japanese psoriasis. Immunogenetics 65: 823–828. doi: 10.1007/s00251-013-0721-x
[41]
Tao YP, Wang WL, Li SY, Zhang J, Shi QZ, et al. (2012) Associations between polymorphisms in IL-12A, IL-12B, IL-12Rbeta1, IL-27 gene and serum levels of IL-12p40, IL-27p28 with esophageal cancer. J Cancer Res Clin Oncol 138: 1891–1900. doi: 10.1007/s00432-012-1269-0
[42]
Wang J, Nong L, Wei Y, Qin S, Zhou Y, et al. (2013) Association of interleukin-12 polymorphisms and serum IL-12p40 levels with osteosarcoma risk. DNA Cell Biol 32: 605–610. doi: 10.1089/dna.2013.2098
[43]
Ong'echa JM, Raballah EO, Kempaiah PM, Anyona SB, Were T, et al. (2011) Polymorphic variability in the 3' untranslated region (UTR) of IL12B is associated with susceptibility to severe anaemia in Kenyan children with acute Plasmodium falciparum malaria. BMC Genet 12: 69. doi: 10.1186/1471-2156-12-69
[44]
Seegers D, Zwiers A, Strober W, Pena AS, Bouma G (2002) A TaqI polymorphism in the 3'UTR of the IL-12 p40 gene correlates with increased IL-12 secretion. Genes Immun 3: 419–423. doi: 10.1038/sj.gene.6363919
[45]
Namkung JH, Lee JE, Kim E, Kim S, Shin ES, et al. (2010) Association of single nucleotide polymorphisms in the IL-12 (IL-12A and B) and IL-12 receptor (IL-12Rbeta1 and beta2) genes and gene-gene interactions with atopic dermatitis in Koreans. J Dermatol Sci 57: 199–206. doi: 10.1016/j.jdermsci.2009.12.003
[46]
Hirschfield GM, Liu X, Xu C, Lu Y, Xie G, et al. (2009) Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 360: 2544–2555. doi: 10.1056/nejmoa0810440
