Abstract
Despite that the association of Behçet’s disease (BD) with the HLA-B5 was first established in the 1970s, a number of recent genome-wide association studies have both confirmed and furthered this association—in various populations—to individual SNPs both inside and outside the HLA. The former include HLA-B, MICA, and HLA-A, while the latter encompass IL10 and IL23R-IL12RB2 regions. The present study examined whether some of these SNPs could be replicated in an Iranian population, where the prevalence of disease is amply documented. Eight SNPs were selected and tested in 552 patients and 417 controls. These were rs7539328, rs12119179, rs1495965, rs1518111, and rs1800871 in IL10 and IL23R-IL12RB2 regions and rs114854070, rs12525170, and rs76546355 (formerly rs116799036) in the HLA locus. The well-known BD-associated genes HLA-B and MICA were independently genotyped. Although we were not able to formally replicate the association with IL10 and IL23R-IL12RB2, we do report that BD in Iran is strongly associated with HLA-B*51, MICA-A6, and the three HLA-linked SNPs (odds ratio (OR) = 3.38, P = 6.21 × 10−14; OR = 2.08, P = 1.58 × 10−13; and OR = 1.67–4.05, P = 1.45 × 10−04 to 4.79 × 10−34, respectively). Our data further indicate that the robust HLA-B/MICA association may be explained by a single variant (rs76546355) between the two genes. Overall, these data contribute to a better appraisal of the intriguing linkage between BD and the ancient Silk Route, spanning from the Mediterranean shores to Japan.
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References
Behcet H, Matteson EL (2010) On relapsing, aphthous ulcers of the mouth, eye and genitalia caused by a virus. 1937. Clin Exp Rheumatol 28:S2–S5
Davatchi F, Tehrani-Banihashemi A, Jamshidi AR, Chams-Davatchi C, Gholami J, Moradi M, Akhlaghi M, Foroozanfar MH, Barghamdi M, Noorolahzadeh E, Samadi F, Hadj-Aliloo M, Ghaznavi K, Soroosh M, Khabazi A, Salari AH, Sharif SK, Karimifar M, Salessi M, Essalat-Manesh K, Nadji A, Shahram F (2008) The prevalence of oral aphthosis in a normal population in Iran: a WHO-ILAR COPCORD study. Arch Iran Med 11:207–209
Davatchi F, Shahram F, Chams-Davatchi C, Shams H, Nadji A, Akhlaghi M, Faezi T, Ghodsi Z, Larimi R, Ashofteh F, Abdollahi BS (2010) Behcet’s disease in Iran: analysis of 6500 cases. Int J Rheum Dis 13:367–373
Gul A, Inanc M, Ocal L, Aral O, Konice M (2000) Familial aggregation of Behcet’s disease in Turkey. Ann Rheum Dis 59:622–625
Hayasaka S, Kurome H, Noda S (1994) HLA antigens in a Japanese family with Behcet’s disease. Graefes Arch Clin Exp Ophthalmol 232:589–590
Hein J, Bottcher K, Grundmann R, Kirchner H, Bein G (1995) Low resolution DNA typing of the HLA-B5 cross-reactive group by nested PCR-SSP. Tissue Antigens 45:27–35
Hughes T, Coit P, Adler A, Yilmaz V, Aksu K, Duzgun N, Keser G, Cefle A, Yazici A, Ergen A, Alpsoy E, Salvarani C, Casali B, Kotter I, Gutierrez-Achury J, Wijmenga C, Direskeneli H, Saruhan-Direskeneli G, Sawalha AH (2013) Identification of multiple independent susceptibility loci in the HLA region in Behcet’s disease. Nat Genet 45:319–324
ICBD (2014) The International Criteria for Behcet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 28:338–347
Kauz R (2010) Aspects of the maritime Silk Road: from the Persian Gulf to the East China Sea. Harrassowitz, Wiesbaden
Meguro A, Inoko H, Ota M, Katsuyama Y, Oka A, Okada E, Yamakawa R, Yuasa T, Fujioka T, Ohno S, Bahram S, Mizuki N (2010) Genetics of Behcet disease inside and outside the MHC. Ann Rheum Dis 69:747–754
Mizuki N, Ota M, Kimura M, Ohno S, Ando H, Katsuyama Y, Yamazaki M, Watanabe K, Goto K, Nakamura S, Bahram S, Inoko H (1997) Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behcet disease. Proc Natl Acad Sci U S A 94:1298–1303
Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, Ito N, Kera J, Okada E, Yatsu K, Song YW, Lee EB, Kitaichi N, Namba K, Horie Y, Takeno M, Sugita S, Mochizuki M, Bahram S, Ishigatsubo Y, Inoko H (2010) Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet’s disease susceptibility loci. Nat Genet 42:703–706
Ohno S, Asanuma T, Sugiura S, Wakisaka A, Aizawa M, Itakura K (1978) HLA-Bw51 and Behcet’s disease. JAMA 240:529
Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C, Le JM, Yang B, Korman BD, Cakiris A, Aglar O, Emrence Z, Azakli H, Ustek D, Tugal-Tutkun I, Akman-Demir G, Chen W, Amos CI, Dizon MB, Kose AA, Azizlerli G, Erer B, Brand OJ, Kaklamani VG, Kaklamanis P, Ben-Chetrit E, Stanford M, Fortune F, Ghabra M, Ollier WE, Cho YH, Bang D, O’Shea J, Wallace GR, Gadina M, Kastner DL, Gul A (2010) Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet’s disease. Nat Genet 42:698–702
Sakane T, Takeno M, Suzuki N, Inaba G (1999) Behcet’s disease. N Engl J Med 341:1284–1291
Xavier JM, Shahram F, Davatchi F, Rosa A, Crespo J, Abdollahi BS, Nadji A, Jesus G, Barcelos F, Patto JV, Shafiee NM, Ghaderibarim F, Oliveira SA (2012) Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behcet’s disease. Arthritis Rheum 64:2761–2772
Zouboulis CC (1999) Epidemiology of Adamantiades-Behcet’s disease. Ann Med Interne (Paris) 150:488–498
Acknowledgments
This study was supported by the Rheumatology Research Center (Tehran University of Medical Sciences), the French association for Behçet’s disease, the Strasbourg High Throughput Next Generation Sequencing facility (GENOMAX), INSERM UMR_S 1109 and Partenariat Hubert Curien GUNDISHAPUR by the ministères des Affaires étrangères et du développement international (MAEDI) and Enseignement supérieur et de la Recherche (MESR), the INSERM Franco-Japanese Nextgen HLA laboratory (FJ-HLA), Laboratoire International Associé (LIA), and the Institut Universitaire de France (IUF).
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Carapito, R., Shahram, F., Michel, S. et al. On the genetics of the Silk Route: association analysis of HLA, IL10, and IL23R-IL12RB2 regions with Behçet’s disease in an Iranian population. Immunogenetics 67, 289–293 (2015). https://doi.org/10.1007/s00251-015-0841-6
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DOI: https://doi.org/10.1007/s00251-015-0841-6