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

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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS LARGE-SCALE WHOLE-EXOME SEQUENCING ANALYSES IDENTIFIED PROTEIN-CODING VARIANTS ASSOCIATED WITH IMMUNE-MEDIATED DISEASES

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references 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. AUTHOR INFORMATION Author notes * Daniel L Kastner

and Elaine F Remmers: These authors jointly directed this work. AUTHORS AND AFFILIATIONS * 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 * Department of Ophthalmology and Visual Science, Yokohama

City University Graduate School of Medicine, Yokohama, Japan Masaki Takeuchi, Nobuhisa Mizuki, Akira Meguro & Tatsukata Kawagoe * 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 * Department of Stem Cell and Immune Regulation,

Yokohama City University Graduate School of Medicine, Yokohama, Japan Yohei Kirino, Atsuhisa Ueda & Yoshiaki Ishigatsubo * Translational Immunology Section, National Institute of

Arthritis and Musculoskeletal and Skin Diseases, US National Institutes of Health, Bethesda, Maryland, USA Mary Blake & Massimo Gadina * Department of Genetics, Institute for

Experimental Medicine, Istanbul University, Istanbul, Turkey Duran Ustek * Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey Ilknur

Tugal-Tutkun * Department of Internal Medicine, Division of Rheumatology, Cerrahpasş a Faculty of Medicine, Istanbul University, Istanbul, Turkey, Emire Seyahi * Department of Ophthalmology,

Cerrahpaşa Faculty of Medicine, Istanbul University, Istanbul, Turkey Yilmaz Ozyazgan * Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal Inês

Sousa, Vânia Francisco & Sofia A Oliveira * Instituto Gulbenkian de Ciência, Oeiras, Portugal Inês Sousa, Vânia Francisco & Sofia A Oliveira * Rheumatology Research Center, Tehran

University of Medical Sciences, Tehran, Iran Fereydoun Davatchi, Farhad Shahram, Bahar Sadeghi Abdollahi, Abdolhadi Nadji, Niloofar Mojarad Shafiee & Fahmida Ghaderibarmi * Department of

Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Shigeaki Ohno * Department of Internal Medicine, Division of Rheumatology, Istanbul Faculty of Medicine,

Istanbul University, Istanbul, Turkey Ahmet Gül Authors * Masaki Takeuchi View author publications You can also search for this author inPubMed Google Scholar * Nobuhisa Mizuki View author

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 Google Scholar * Bahar Sadeghi Abdollahi View author publications You can also search for this author inPubMed Google Scholar * Abdolhadi Nadji View author publications You can also search

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publications You can also search for this author inPubMed Google Scholar * Shigeaki Ohno View author publications You can also search for this author inPubMed Google Scholar * Atsuhisa Ueda

View author publications You can also search for this author inPubMed Google Scholar * Yoshiaki Ishigatsubo View author publications You can also search for this author inPubMed Google

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this author inPubMed Google Scholar * Elaine F Remmers View author publications You can also search for this author inPubMed Google Scholar 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.

ETHICS DECLARATIONS COMPETING INTERESTS 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) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE

THIS ARTICLE 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 Download citation * Received: 12 September 2016 * Accepted: 12 January 2017 * Published: 06 February 2017 * Issue Date: March

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