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Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility

Nature Genetics volume 49, pages 438–443 (2017)Cite this article

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Abstract

We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A–IL1B, IRF8, and CEBPB–PTPN1, with genome-wide significance (P < 5 × 10−8) by direct genotyping and ADO–EGR2 by imputation. We replicated the ADO–EGR2, IRF8, and CEBPB–PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO–EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A–IL1B, was associated with both decreased IL-1α and increased IL-1β production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10−15). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.

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Figure 1: Association of Immunochip markers with Behçet's disease in 1,900 cases and 1,779 controls from Turkey.
Figure 2: Expression analysis according to genotype at rs4402765, the lead SNP in the IL1A–IL1B locus.

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Acknowledgements

This research was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. We thank all the patients, the healthy controls, and medical staff for their enthusiastic support during this research study. M.T. is supported by a Fellowship for Japanese Biomedical and Behavioral Researchers at the NIH from the Japan Society for the Promotion of Science Research and a grant from the Japan Foundation for Applied Enzymology. Y.K. is supported by grants from the Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (grant 26713036), the Kanae Foundation for the Promotion of Medical Science, the Takeda Science Foundation, the SENSHIN Medical Research Foundation, and the Yokohama Foundation for Advancement of Medical Science. This research was also supported by the Portuguese Fundação para a Ciência e a Tecnologia (grant CMUP-ERI/TPE/0028/2013, fellowship SFRH/BPD/70008/2010 to I.S., and an Investigator-FCT contract to S.A.O.) and the Research Committee of the Tehran University of Medical Sciences (grant 132/714). We thank A.F. Wilson for insightful comments on this manuscript.

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Author notes

  1. Daniel L Kastner and Elaine F Remmers: These authors jointly directed this work.

Authors and Affiliations

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

    Masaki Takeuchi, Colleen Satorius, Julie Le, Burak Erer, Daniel L Kastner & Elaine F Remmers

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

    Masaki Takeuchi, Nobuhisa Mizuki, Akira Meguro & Tatsukata Kawagoe

  3. Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Michael J Ombrello

  4. Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Yohei Kirino, Atsuhisa Ueda & Yoshiaki Ishigatsubo

  5. Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Mary Blake & Massimo Gadina

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

    Duran Ustek

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

    Ilknur Tugal-Tutkun

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

    Emire Seyahi

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

    Yilmaz Ozyazgan

  10. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

    Inês Sousa, Vânia Francisco & Sofia A Oliveira

  11. Instituto Gulbenkian de Ciência, Oeiras, Portugal

    Inês Sousa, Vânia Francisco & Sofia A Oliveira

  12. Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Fereydoun Davatchi, Farhad Shahram, Bahar Sadeghi Abdollahi, Abdolhadi Nadji, Niloofar Mojarad Shafiee & Fahmida Ghaderibarmi

  13. Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    Shigeaki Ohno

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

    Ahmet Gül

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  1. Masaki Takeuchi
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Contributions

M.T., M.J.O., A.G., D.L.K., and E.F.R. designed the study. M.T., A.M., M.J.O., M.B., M.G., A.G., D.L.K., and E.F.R. carried out the analysis. M.T., N.M., A.M., M.J.O., Y.K., C.S., J.L., M.B., B.E., T.K., D.U., I.T.-T., E.S., Y.O., I.S., F.D., V.F., F.S., B.S.A., A.N., N.M.S., F.G., S.O., A.U., Y.I., M.G., S.A.O., A.G., D.L.K., and E.F.R. procured samples and generated data. M.T., M.J.O., M.B., M.G., A.G., D.L.K., and E.F.R. wrote the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Daniel L Kastner or Elaine F Remmers.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–21 (PDF 2510 kb)

Supplementary Data Set

Immunochip statistical summary data set (TXT 655 kb)

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Takeuchi, M., Mizuki, N., Meguro, A. et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility. Nat Genet 49, 438–443 (2017). https://doi.org/10.1038/ng.3786

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