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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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.
Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note.
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Nature Communications (2018)