Abstract

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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References

  1. 1.

    , , , & HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum. 61, 1287–1296 (2009).

  2. 2.

    et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behçet disease. Proc. Natl. Acad. Sci. USA 94, 1298–1303 (1997).

  3. 3.

    et al. Localization of the pathogenic gene of Behçet's disease by microsatellite analysis of three different populations. Invest. Ophthalmol. Vis. Sci. 41, 3702–3708 (2000).

  4. 4.

    , , , & Association of major histocompatibility complex class I chain–related gene A and HLA-B alleles with Behçet's disease in Turkey. Jpn. J. Ophthalmol. 51, 431–436 (2007).

  5. 5.

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

  6. 6.

    et al. Genetic association of HLA-A* 2601 with ocular Behçet's disease in Japanese patients. Clin. Exp. Rheumatol. 28, S39–S44 (2010).

  7. 7.

    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. 42, 698–702 (2010).

  8. 8.

    et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat. Genet. 42, 703–706 (2010).

  9. 9.

    et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat. Genet. 43, 1193–1201 (2011).

  10. 10.

    , , & HLA* IMP—an integrated framework for imputing classical HLA alleles from SNP genotypes. Bioinformatics 27, 968–972 (2011).

  11. 11.

    et al. The critical region for Behçet disease in the human major histocompatibility complex is reduced to a 46-kb segment centromeric of HLA-B, by association analysis using refined microsatellite mapping. Am. J. Hum. Genet. 64, 1406–1410 (1999).

  12. 12.

    et al. Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 78, 827–851 (2006).

  13. 13.

    et al. HLA-Cw*1602: a new susceptibility marker of Behçet's disease in southern Spain. Tissue Antigens 51, 111–114 (1998).

  14. 14.

    et al. New insights of HLA class I association to Behçet's disease in Portuguese patients. Tissue Antigens 72, 379–382 (2008).

  15. 15.

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

  16. 16.

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

  17. 17.

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

  18. 18.

    1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).

  19. 19.

    , & A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

  20. 20.

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

Download references

Acknowledgements

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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Affiliations

  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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Contributions

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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DOI

https://doi.org/10.1038/ng.2551