Behçet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçet's disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçet's disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10−50). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10−26), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10−14) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10−18) were also identified and replicated.

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Funding for this project was provided by the Rheumatology Research Foundation's Rheumatology Investigator award to A.H.S. Genotyping of the Italian controls has been made possible by grants from the Celiac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch government, grant BSIK03009 to C.W.) and the Netherlands Organization for Scientific Research (NWO-VICI grant 918.66.620 to C.W.).

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  1. Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA.

    • Travis Hughes
    • , Patrick Coit
    •  & Amr H Sawalha
  2. Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.

    • Adam Adler
  3. Department of Physiology, Istanbul University, Istanbul School of Medicine, Istanbul, Turkey.

    • Vuslat Yilmaz
    •  & Güher Saruhan-Direskeneli
  4. Department of Rheumatology, Ege University, School of Medicine, Izmir, Turkey.

    • Kenan Aksu
    •  & Gokhan Keser
  5. Department of Rheumatology, Ankara University, Faculty of Medicine, Ankara, Turkey.

    • Nursen Düzgün
  6. Department of Rheumatology, Kocaeli University, School of Medicine, Kocaeli, Turkey.

    • Ayse Cefle
    •  & Ayten Yazici
  7. Ophthalmology Clinic, Okmeydanı Research and Education Hospital, Istanbul, Turkey.

    • Andac Ergen
  8. Department of Dermatology, Akdeniz University School of Medicine, Antalya, Turkey.

    • Erkan Alpsoy
  9. Rheumatology Unit, Department of Internal Medicine, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy.

    • Carlo Salvarani
  10. Molecular Biology Laboratory, Azienda Ospedaliera Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico, Reggio Emilia, Italy.

    • Bruno Casali
  11. Department of Internal Medicine II, University Hospital Tuebingen, Tuebingen, Germany.

    • Ina Kötter
  12. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

    • Javier Gutierrez-Achury
    •  & Cisca Wijmenga
  13. Department of Rheumatology, Marmara University, School of Medicine, Istanbul, Turkey.

    • Haner Direskeneli


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T.H. performed data analysis and contributed to data interpretation and to the writing of the manuscript. P.C. contributed to performing the experiments and to data analysis. A.A. performed genotyping experiments. V.Y., K.A., N.D., G.K., A.C., A.Y., A.E., E.A., C.S., B.C. and I.K. provided samples for the study. J.G.-A. and C.W. provided genotyping data from Italian controls for the study. H.D. and G.S.-D. provided samples and contributed to the organization of the study. A.H.S. designed and conceived the study, directed the analysis, interpreted the data and wrote the manuscript. All authors contributed to critically reviewing the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Amr H Sawalha.

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