Letter | Published:

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

Nature Genetics 42, 703–706 (2010) | Download Citation

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).

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

References

  1. 1.

    , & Behcet's disease. Semin. Arthritis Rheum. 27, 197–217 (1998).

  2. 2.

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

  3. 3.

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

  4. 4.

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

  5. 5.

    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. 6.

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

  7. 7.

    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).

  8. 8.

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

  9. 9.

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

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 13.

    , & 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).

  14. 14.

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

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

    , , & Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

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

    • Nobuhisa Mizuki
    •  & Akira Meguro

    These authors contributed equally to this work.

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. Search for Nobuhisa Mizuki in:

  2. Search for Akira Meguro in:

  3. Search for Masao Ota in:

  4. Search for Shigeaki Ohno in:

  5. Search for Tomoko Shiota in:

  6. Search for Tatsukata Kawagoe in:

  7. Search for Norihiko Ito in:

  8. Search for Jiro Kera in:

  9. Search for Eiichi Okada in:

  10. Search for Keisuke Yatsu in:

  11. Search for Yeong-Wook Song in:

  12. Search for Eun-Bong Lee in:

  13. Search for Nobuyoshi Kitaichi in:

  14. Search for Kenichi Namba in:

  15. Search for Yukihiro Horie in:

  16. Search for Mitsuhiro Takeno in:

  17. Search for Sunao Sugita in:

  18. Search for Manabu Mochizuki in:

  19. Search for Seiamak Bahram in:

  20. Search for Yoshiaki Ishigatsubo in:

  21. Search for Hidetoshi Inoko in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Nobuhisa Mizuki or Hidetoshi Inoko.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–5

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

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

Further reading