Abstract

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10−17). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10−3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10−20, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.

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Acknowledgements

We are grateful to all subjects and control probands for participation in this study. We thank P. Rothe, M. Kirsch, P. Badorf, P. Gilbert and K. Krause for excellent technical assistance. We thank D. Fried for helping with the cloning of constructs. The work was supported in part by a grant from the Interdisciplinary Centre for Clinical Research (IZKF B32/A8) of the University of Erlangen-Nuremberg and a grant from the ELAN fund (Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsförderung) of the University of Erlangen-Nuremberg. The KORA (Cooperative Health Research in the Region of Augsburg) research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. We acknowledge the National Institute for Health Research, Manchester Biomedical Research Centre and Science Foundation Ireland for support. A.B., I.N.B. and J.B. are funded by Arthritis Research. H.B. and F.B. were supported by a research grant of Wyeth Pharma GmbH, Germany (Forschungsförderungspreis Rheumatologie 2008). E.G. and G.N. are funded by the ADIPSO (Association for the Defense of Psoriasis Patients). The Irish control DNA was provided by the Irish Blood Transfusion Service and Trinity College Dublin population DNA Biobank. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. U.H., E.G., E.K., M.A., P.H., I.N.B., F.B., O.F., G.-M.A., N.J.M., G.N., H.B., A.B. and A.R. are members of the Psoriatic Arthritis Genetics in Europe (PAGE) Consortium.

Author information

Author notes

    • Jesús Lascorz

    Present address: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Ulrike Hüffmeier
    •  & Steffen Uebe

    These authors contributed equally to this work.

    • Harald Burkhardt
    • , Anne Barton
    •  & André Reis

    These authors jointly supervised this work.

Affiliations

  1. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.

    • Ulrike Hüffmeier
    • , Steffen Uebe
    • , Arif B Ekici
    • , Maria Apel
    • , Jesús Lascorz
    •  & André Reis
  2. Arthritis Research UK Epidemiology Unit, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.

    • John Bowes
    • , Pauline Ho
    • , Ian N Bruce
    •  & Anne Barton
  3. Department of Biopathology, Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, School of Medicine, University of Rome 'Tor Vergata' and Fondazione PTV 'Policlinico Tor Vergata', Rome, Italy.

    • Emiliano Giardina
    •  & Giuseppe Novelli
  4. Royal National Hospital for Rheumatic Diseases, Bath, UK.

    • Eleanor Korendowych
    •  & Neil J McHugh
  5. Department of Public Health and Clinical Medicine, Rheumatology, University Hospital, Umeå, Sweden.

    • Kristina Juneblad
    •  & Gerd-Marie Alenius
  6. Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Ross McManus
    •  & Anthony W Ryan
  7. Division of Rheumatology, Department of Internal Medicine II, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.

    • Frank Behrens
    • , Beate Böhm
    •  & Harald Burkhardt
  8. Department of Dermatology, University of Münster, Münster, Germany.

    • Heiko Traupe
  9. Psoriasis Rehabilitation Hospital, Bad Bentheim, Germany.

    • Jörg Lohmann
  10. Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany.

    • Christian Gieger
    •  & Heinz-Erich Wichmann
  11. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Heinz-Erich Wichmann
  12. Klinikum Grosshadern, Munich, Germany.

    • Heinz-Erich Wichmann
  13. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany.

    • Christine Herold
    • , Michael Steffens
    •  & Thomas F Wienker
  14. Karolinska Institute, Stockholm, Sweden.

    • Lars Klareskog
  15. Department of Rheumatology, St. Vincent's University Hospital, University College Dublin (UCD) School of Medicine and Medical Science and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.

    • Oliver FitzGerald
  16. Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.

    • Neil J McHugh

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Contributions

H.B., A.B. and A.R. designed the study and worked out its concept. U.H., A.B.E., M.A. and J.B. planned and performed genotyping with genome-wide arrays and/or assays for single SNPs, and U.H., S.U., A.B.E., J.B., M.A., C.H., M.S., T.F.W. and A.R. analyzed genetic data. B.B. and H.B. performed functional studies. U.H., J.B., E.G., E.K., K.J., R.M., P.H., I.N.B., A.W.R., F.B., J. Lascorz, H.T., J. Lohmann, C.G., H.-E.W., O.F., G.-M.A., N.J.M., G.N., H.B. and A.B. recruited subjects and control individuals and collected the phenotypic data. U.H., S.U., H.B. and A.R. wrote a first draft of the manuscript. A.B. edited the manuscript in a major way. All authors reviewed and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to André Reis.

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DOI

https://doi.org/10.1038/ng.688

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