Letter | Published:

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Nature Genetics 42, 698–702 (2010) | Download Citation

Subjects

Abstract

Behçet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 × 10−8). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 × 10−18, odds ratio = 1.45, 95% CI 1.34–1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 × 10−9, OR = 1.28, 95% CI 1.18–1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

Accessions

GenBank/EMBL/DDBJ

References

  1. 1.

    , , , & Familial aggregation of Behcet's disease in Turkey. Ann. Rheum. Dis. 59, 622–625 (2000).

  2. 2.

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

  3. 3.

    et al. Evidence for linkage of the HLA-B locus in Behcet's disease, obtained using the transmission disequilibrium test. Arthritis Rheum. 44, 239–240 (2001).

  4. 4.

    et al. Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study. Arthritis Res. Ther. 11, R66 (2009).

  5. 5.

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

  6. 6.

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

  7. 7.

    et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet's disease susceptibility loci. Nat. Genet. advance online publication, doi:10.1038/ng.624 (11 July 2010).

  8. 8.

    et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

  9. 9.

    et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

  10. 10.

    et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

  11. 11.

    et al. IL-10 genotype analysis in patients with Behcet's disease. Hum. Immunol. 68, 122–127 (2007).

  12. 12.

    et al. Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum. 42, 1101–1108 (1999).

  13. 13.

    et al. Alleles carried at positions -819 and -592 of the IL10 promoter affect transcription following stimulation of peripheral blood cells with Streptococcus pneumoniae. Immunogenetics 55, 629–632 (2003).

  14. 14.

    et al. An investigation of polymorphism in the interleukin-10 gene promoter. Eur. J. Immunogenet. 24, 1–8 (1997).

  15. 15.

    , , & Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

  16. 16.

    et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

  17. 17.

    et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

  18. 18.

    et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).

  19. 19.

    et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

  20. 20.

    , & Role of toll-like receptors in spontaneous commensal-dependent colitis. Immunity 25, 319–329 (2006).

  21. 21.

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

  22. 22.

    , , , & Role of polymorphisms in Adamantiades-Behcet's disease. J. Rheumatol. 35, 2376–2378 (2008).

  23. 23.

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

  24. 24.

    Haploview: visualization and analysis of SNP genotype data. Cold Spring Harb. Protoc. pdb ip71 (2009).

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the US National Institutes of Health, by the Istanbul University Research Fund and by the UK Behçet's Syndrome Society. This work was also supported in the part by US NIH grants to C.I.A. (AR44422 and PC30CA016772). We thank all of our subjects for their enthusiastic support of our studies aiming to understand and find better treatments for Behçet's disease, and we thank O. Aksakalli and H. Ustek for their help in blood collection.

Author information

Affiliations

  1. Laboratory of Clinical Investigation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.

    • Elaine F Remmers
    • , Yohei Kirino
    • , Michael J Ombrello
    • , Colleen Satorius
    • , Julie M Le
    • , Benjamin D Korman
    •  & Daniel L Kastner

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

    • Fulya Cosan
    • , Burak Erer
    •  & Ahmet Gül

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

    • Neslihan Abaci
    • , Aris Cakiris
    • , Oznur Aglar
    • , Zeliha Emrence
    • , Hulya Azakli
    • , Duran Ustek
    •  & Ahmet Gül

  4. Translational Immunology Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.

    • Barbara Yang
    • , Michael B Dizon
    •  & Massimo Gadina

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

    • Ilknur Tugal-Tutkun

  6. Istanbul Faculty of Medicine, Department of Neurology, Istanbul University, Istanbul, Turkey.

    • Gulsen Akman-Demir

  7. University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Wei Chen
    •  & Christopher I Amos

  8. Istanbul Faculty of Medicine, Department of Dermatology, Istanbul University, Istanbul, Turkey.

    • Afet Akdag Kose
    •  & Gulsevim Azizlerli

  9. School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

    • Oliver J Brand

  10. Translational Breast Cancer Research Division Hematology and Oncology Northwestern University, Chicago, Illinois, USA.

    • Virginia G Kaklamani

  11. Department of Rheumatology, Athens Medical Center, Greece.

    • Phaedon Kaklamanis

  12. Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

    • Eldad Ben-Chetrit

  13. King's College, London, UK.

    • Miles Stanford

  14. Queen Mary's College, London, UK.

    • Farida Fortune

  15. University Hospital, Damascus, Syria.

    • Marwen Ghabra

  16. Centre for Integrated Genomic Medical Research, School of Immunity and Infection, University of Manchester, Manchester, UK.

    • William E R Ollier

  17. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.

    • Young-Hun Cho

  18. Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.

    • Dongsik Bang

  19. Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.

    • John O'Shea

  20. Academic Unit of Ophthalmology, University of Birmingham, Birmingham, UK.

    • Graham R Wallace

Authors

  1. Search for Elaine F Remmers in:

  2. Search for Fulya Cosan in:

  3. Search for Yohei Kirino in:

  4. Search for Michael J Ombrello in:

  5. Search for Neslihan Abaci in:

  6. Search for Colleen Satorius in:

  7. Search for Julie M Le in:

  8. Search for Barbara Yang in:

  9. Search for Benjamin D Korman in:

  10. Search for Aris Cakiris in:

  11. Search for Oznur Aglar in:

  12. Search for Zeliha Emrence in:

  13. Search for Hulya Azakli in:

  14. Search for Duran Ustek in:

  15. Search for Ilknur Tugal-Tutkun in:

  16. Search for Gulsen Akman-Demir in:

  17. Search for Wei Chen in:

  18. Search for Christopher I Amos in:

  19. Search for Michael B Dizon in:

  20. Search for Afet Akdag Kose in:

  21. Search for Gulsevim Azizlerli in:

  22. Search for Burak Erer in:

  23. Search for Oliver J Brand in:

  24. Search for Virginia G Kaklamani in:

  25. Search for Phaedon Kaklamanis in:

  26. Search for Eldad Ben-Chetrit in:

  27. Search for Miles Stanford in:

  28. Search for Farida Fortune in:

  29. Search for Marwen Ghabra in:

  30. Search for William E R Ollier in:

  31. Search for Young-Hun Cho in:

  32. Search for Dongsik Bang in:

  33. Search for John O'Shea in:

  34. Search for Graham R Wallace in:

  35. Search for Massimo Gadina in:

  36. Search for Daniel L Kastner in:

  37. Search for Ahmet Gül in:

Contributions

Study design: E.F.R., F.C., Y.K., M.J.O., B.D.K., D.U., W.C., C.I.A., J.O., M. Gadina, D.L.K., A.G. Analysis: E.F.R., Y.K., M.J.O., B.Y., W.C., C.I.A., M.B.D., G.R.W., M. Gadina, D.L.K., A.G. Sample procurement and data generation: E.F.R., F.C., Y.K., M.J.O., N.A., C.S., J.M.L., B.Y., B.D.K., A.C., O.A., Z.E., H.A., D.U., I.T.-T., G.A.-D., W.C., C.I.A., M.B.D., A.A.K., G.A., B.E., O.J.B., V.G.K., P.K., E.B.-C., M.S., F.F., M. Ghabra., W.E.R.O., Y.-H.C., D.B., J.O., G.R.W., M. Gadina, D.L.K., A.G. Writing: E.F.R., Y.K., M.J.O., B.Y., C.I.A., J.O., M. Gadina, D.L.K., A.G.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Elaine F Remmers.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–3 and Supplementary Figures 1–5

To obtain permission to re-use content from this article visit RightsLink.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.625

Further reading Further reading