Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci

Nature Genetics volume 42, pages 703–706 (2010)Cite this article

Subjects

Abstract

Behçet's disease is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent ocular symptoms, oral and genital ulcers and skin lesions1. We conducted a genome-wide association study in a Japanese cohort including 612 individuals with Behçet's disease and 740 unaffected individuals (controls). We identified two suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, P = 2.7 × 10−8) and 1q32.1 (IL10, rs1554286, P = 8.0 × 10−8). A meta-analysis of these two loci with results from additional Turkish and Korean cohorts showed genome-wide significant associations (rs1495965 in IL23R-IL12RB2, P = 1.9 × 10−11, odds ratio = 1.35; rs1800871 in IL10, P = 1.0 × 10−14, odds ratio = 1.45).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overview of SNPs across the HLA region in the GWAS.
Figure 2: In-depth SNP analysis in target areas.

Similar content being viewed by others

References

  1. Kaklamani, V.G., Vaiopoulos, G. & Kaklamanis, P.G. Behcet's disease. Semin. Arthritis Rheum. 27, 197–217 (1998).

    Article  CAS  Google Scholar 

  2. Ohno, S. et al. Close association of HLA-Bw51 with Behcet's disease. Arch. Ophthalmol. 100, 1455–1458 (1982).

    Article  CAS  Google Scholar 

  3. 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 

  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. Remmers, E.F. 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. advance online publication, doi:10.1038/ng.625 (11 July 2010).

  6. 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 

  7. 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 

  8. Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).

    Article  Google Scholar 

  9. Hirschfield, G.M. et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N. Engl. J. Med. 360, 2544–2555 (2009).

    Article  CAS  Google Scholar 

  10. Rueda, B. et al. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann. Rheum. Dis. 67, 1451–1454 (2008).

    Article  CAS  Google Scholar 

  11. Isomura, M. et al. IL12RB2 and ABCA1 genes are associated with susceptibility to radiation dermatitis. Clin. Cancer Res. 14, 6683–6689 (2008).

    Article  CAS  Google Scholar 

  12. Iwakura, Y. & Ishigame, H. The IL-23/IL-17 axis in inflammation. J. Clin. Invest. 116, 1218–1222 (2006).

    Article  CAS  Google Scholar 

  13. Chang, J.T., Shevach, E.M. & Segal, B.M. Regulation of interleukin (IL)-12 receptor beta2 subunit expression by endogenous IL-12: a critical step in the differentiation of pathogenic autoreactive T cells. J. Exp. Med. 189, 969–978 (1999).

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

    Article  CAS  Google Scholar 

  16. Mizushima, Y. Recent research into Behçet's disease in Japan. Int. J. Tissue React. 10, 59–65 (1998).

    Google Scholar 

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

  18. 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 

  19. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  20. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We sincerely thank the individuals with Behçet's disease who participated in this study. This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan; a grant from the Ministry of Health, Labour and Welfare, Japan; a grant from Menicon Co., Ltd.; and a grant from the Johnson & Johnson KK Vision Care Company. The laboratory of S.B. was supported by the Agence Nationale pour la Recherche (ANR), the Fédération des Maladies Orphelines and the Association française de la maladie de Behçet.

Author information

Author notes

  1. Nobuhisa Mizuki and Akira Meguro: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan

    Nobuhisa Mizuki, Akira Meguro, Tomoko Shiota, Tatsukata Kawagoe, Norihiko Ito & Jiro Kera

  2. Department of Legal Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan

    Masao Ota

  3. Department of Ocular Inflammation and Immunology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Hokkaido, Japan

    Shigeaki Ohno

  4. Okada Eye Clinic, Konan-ku, Yokohama, Kanagawa, Japan

    Eiichi Okada

  5. Department of Molecular Life Science, Division of Molecular Medical Science and Molecular Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan

    Keisuke Yatsu & Hidetoshi Inoko

  6. Department of Internal Medicine, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea

    Yeong-Wook Song & Eun-Bong Lee

  7. Department of Ophthalmology, Health Sciences University of Hokkaido, Kita-ku, Sapporo, Hokkaido, Japan

    Nobuyoshi Kitaichi

  8. Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Hokkaido, Japan

    Kenichi Namba & Yukihiro Horie

  9. Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Kanagawa, Japan

    Mitsuhiro Takeno & Yoshiaki Ishigatsubo

  10. Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University Graduate School of Medical and Dental Sciences, Bunkyo-ku, Tokyo, Japan

    Sunao Sugita & Manabu Mochizuki

  11. Laboratoire d'Immunogénétique Moléculaire Humaine, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Université de Strasbourg, Strasbourg, Cedex, France

    Seiamak Bahram

  12. Laboratoire Central d'Immunologie, Plateau Technique de Biologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, Cedex, France

    Seiamak Bahram

Authors
  1. Nobuhisa Mizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akira Meguro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masao Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shigeaki Ohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomoko Shiota
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tatsukata Kawagoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Norihiko Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiro Kera
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eiichi Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Keisuke Yatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yeong-Wook Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eun-Bong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nobuyoshi Kitaichi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kenichi Namba
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yukihiro Horie
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Mitsuhiro Takeno
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Sunao Sugita
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Manabu Mochizuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Seiamak Bahram
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Yoshiaki Ishigatsubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Hidetoshi Inoko
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.M. designed and supervised the experiment, provided study samples, performed data analysis and wrote the manuscript. A.M. designed the experiment, performed the SNP selection, supervised genotyping, performed data analysis, wrote the manuscript and prepared the tables and figures. M.O. participated in the experimental design, helped with data analysis and edited the manuscript. S.O. participated in the experimental design, provided study samples and edited the manuscript. T.S., T.K., N.I. and K.Y. performed genotyping. J.K. helped with data analysis. E.O., Y.W.S., E.B.L., N.K., K.N., Y.H., M.T., S.S., M.M. and Y.I. provided study samples. S.B. participated in the experimental design, helped with data analysis and participated in critical revisions of the manuscript. H.I. participated in the experimental design, provided study samples, helped with data analysis and edited the manuscript.

Corresponding authors

Correspondence to Nobuhisa Mizuki or Hidetoshi Inoko.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–5 (PDF 200 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mizuki, N., Meguro, A., Ota, M. et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat Genet 42, 703–706 (2010). https://doi.org/10.1038/ng.624

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.624

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing