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Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1

Nature Genetics volume 45, pages 202–207 (2013)Cite this article

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Abstract

Individuals with Behçet's disease suffer from episodic inflammation often affecting the orogenital mucosa, skin and eyes. To discover new susceptibility loci for Behçet's disease, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behçet's disease and 1,278 controls. We identified new associations at CCR1, STAT4 and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis P < 2 × 10−9). We also found evidence for interaction between HLA-B*51 and ERAP1 (P = 9 × 10−4). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I–ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behçet's disease.

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Figure 1: Manhattan plot of imputed SNPs.
Figure 2: Regional association plots.
Figure 3: Epistasis between HLA-B*51 and ERAP1 rs17482078 (ERAP1 p.Arg725Gln) coding variant in Behçet's disease.
Figure 4: Association of CCR1 and STAT4 variants with gene expression levels and function in human cells.

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Acknowledgements

This research was supported by the Intramural Research Programs of the National Human Genome Research Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Center for Human Immunology, Autoimmunity and Inflammation of the US National Institutes of Health, and by the Istanbul University Research Fund, the Research on Specific Disease of the Health Science Research Grants from the Japanese Ministry of Health, Labor, and Welfare, and the Japan Rheumatism Foundation. We thank A. Wilson for helpful comments on this manuscript.

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Author notes

  1. Yohei Kirino and George Bertsias: These authors contributed equally to this work.

  2. Ahmet Gül, Elaine F Remmers and Daniel L Kastner: These authors jointly directed this work.

Authors and Affiliations

  1. Inflammatory Disease Section, Medical Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA

    Yohei Kirino, George Bertsias, Colleen Satorius, Geryl M Wood, Michael J Ombrello, Elaine F Remmers & Daniel L Kastner

  2. Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Yohei Kirino, Yoshiaki Ishigatsubo, Atsuhisa Ueda & Mitsuhiro Takeno

  3. Rheumatology, Clinical Immunology, and Allergy, Faculty of Medicine, University of Crete, Iraklion, Greece

    George Bertsias

  4. Department of Ophthalmology and Visual Science, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Nobuhisa Mizuki & Akira Meguro

  5. Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Ilknur Tugal-Tutkun

  6. Department of Internal Medicine, Division of Rheumatology, Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Emire Seyahi & F Sevgi Sacli

  7. Department of Ophthalmology, Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Yilmaz Ozyazgan

  8. Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Burak Erer & Ahmet Gül

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

    Hidetoshi Inoko

  10. Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey

    Zeliha Emrence, Atilla Cakar, Neslihan Abaci & Duran Ustek

  11. Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, US National Institutes of Health, Baltimore, Maryland, USA

    Yoonhee Kim

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Contributions

The study was designed by Y. Kirino, G.B., A.G., M.J.O., E.F.R. and D.L.K. Analysis was carried out by Y. Kirino, G.B., Y. Kim, A.M., A.G., E.F.R. and D.L.K. Sample procurement and data generation were performed by Y. Kirino, G.B., Y.I., N.M., I.T.-T., E.S., Y.O., F.S.S., B.E., H.I., Z.E., A.C., N.A., D.U., C.S., A.U., M.T., Y. Kim, G.M.W., M.J.O., A.M., A.G., E.F.R. and D.L.K. The manuscript was written by Y. Kirino, G.B., Y. Kim, M.J.O., A.G., E.F.R. and D.L.K. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Ahmet Gül, Elaine F Remmers or Daniel L Kastner.

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Kirino, Y., Bertsias, G., Ishigatsubo, Y. et al. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nat Genet 45, 202–207 (2013). https://doi.org/10.1038/ng.2520

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