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Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Abstract

Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 × 10−8). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 × 10−18, odds ratio = 1.45, 95% CI 1.34–1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 × 10−9, OR = 1.28, 95% CI 1.18–1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

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Figure 1: Behçet's disease genome-wide association results.
Figure 2: Analysis of associations within the MHC region.
Figure 3: Fine-mapping of the IL10 and IL23R-IL12RB2 regions.
Figure 4: Expression analysis of IL10.

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References

  1. Gül, A., Inanc, M., Ocal, L., Aral, O. & Konice, M. Familial aggregation of Behcet's disease in Turkey. Ann. Rheum. Dis. 59, 622–625 (2000).

    Article  Google Scholar 

  2. de Menthon, M., Lavalley, M.P., Maldini, C., Guillevin, L. & Mahr, A. HLA-B51/B5 and the risk of Behcet's disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum. 61, 1287–1296 (2009).

    Article  CAS  Google Scholar 

  3. Gül, A. et al. Evidence for linkage of the HLA-B locus in Behcet's disease, obtained using the transmission disequilibrium test. Arthritis Rheum. 44, 239–240 (2001).

    Article  Google Scholar 

  4. Fei, Y. et al. Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study. Arthritis Res. Ther. 11, R66 (2009).

    Article  Google Scholar 

  5. Meguro, A. et al. Genetics of Behcet's disease inside and outside the MHC. Ann. Rheum. Dis. 69, 747–754 (2010).

    Article  CAS  Google Scholar 

  6. Mizuki, N. et al. 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. USA 94, 1298–1303 (1997).

    Article  CAS  Google Scholar 

  7. Mizuki, N. et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat. Genet. advance online publication, doi:10.1038/ng.624 (11 July 2010).

  8. Burton, P.R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

    Article  CAS  Google Scholar 

  9. Cargill, M. et al. 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 (2007).

    Article  CAS  Google Scholar 

  10. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  Google Scholar 

  11. Wallace, G.R. et al. IL-10 genotype analysis in patients with Behcet's disease. Hum. Immunol. 68, 122–127 (2007).

    Article  CAS  Google Scholar 

  12. Crawley, E. et al. Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum. 42, 1101–1108 (1999).

    Article  CAS  Google Scholar 

  13. Temple, S.E. et al. Alleles carried at positions -819 and -592 of the IL10 promoter affect transcription following stimulation of peripheral blood cells with Streptococcus pneumoniae. Immunogenetics 55, 629–632 (2003).

    Article  CAS  Google Scholar 

  14. Turner, D.M. et al. An investigation of polymorphism in the interleukin-10 gene promoter. Eur. J. Immunogenet. 24, 1–8 (1997).

    Article  CAS  Google Scholar 

  15. Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  Google Scholar 

  16. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

    Article  CAS  Google Scholar 

  17. Barrett, J.C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

    Article  CAS  Google Scholar 

  18. Gateva, V. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).

    Article  CAS  Google Scholar 

  19. Glocker, E.O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    Article  CAS  Google Scholar 

  20. Rakoff-Nahoum, S., Hao, L. & Medzhitov, R. Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329 (2006).

    Article  CAS  Google Scholar 

  21. Criteria for diagnosis of Behcet's disease. International Study Group for Behcet's Disease. Lancet 335, 1078–1080 (1990).

  22. Kaklamani, V.G., Sadim, M., Koumantaki, Y., Kaklamanis, P. & Pasche, B. Role of polymorphisms in Adamantiades-Behcet's disease. J. Rheumatol. 35, 2376–2378 (2008).

    Article  Google Scholar 

  23. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  24. Barrett, J.C. Haploview: visualization and analysis of SNP genotype data. Cold Spring Harb. Protoc. pdb ip71 (2009).

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the US National Institutes of Health, by the Istanbul University Research Fund and by the UK Behçet's Syndrome Society. This work was also supported in the part by US NIH grants to C.I.A. (AR44422 and PC30CA016772). We thank all of our subjects for their enthusiastic support of our studies aiming to understand and find better treatments for Behçet's disease, and we thank O. Aksakalli and H. Ustek for their help in blood collection.

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Study design: E.F.R., F.C., Y.K., M.J.O., B.D.K., D.U., W.C., C.I.A., J.O., M. Gadina, D.L.K., A.G. Analysis: E.F.R., Y.K., M.J.O., B.Y., W.C., C.I.A., M.B.D., G.R.W., M. Gadina, D.L.K., A.G. Sample procurement and data generation: E.F.R., F.C., Y.K., M.J.O., N.A., C.S., J.M.L., B.Y., B.D.K., A.C., O.A., Z.E., H.A., D.U., I.T.-T., G.A.-D., W.C., C.I.A., M.B.D., A.A.K., G.A., B.E., O.J.B., V.G.K., P.K., E.B.-C., M.S., F.F., M. Ghabra., W.E.R.O., Y.-H.C., D.B., J.O., G.R.W., M. Gadina, D.L.K., A.G. Writing: E.F.R., Y.K., M.J.O., B.Y., C.I.A., J.O., M. Gadina, D.L.K., A.G.

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Correspondence to Elaine F Remmers.

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The authors declare no competing financial interests.

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Supplementary Tables 1–3 and Supplementary Figures 1–5 (PDF 830 kb)

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Remmers, E., 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. Nat Genet 42, 698–702 (2010). https://doi.org/10.1038/ng.625

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