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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Ibrahim, G., Waxman, R. & Helliwell, P.S. The prevalence of psoriatic arthritis in people with psoriasis. Arthritis Rheum. 61, 1373–1378 (2009).
Taylor, W. et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 54, 2665–2673 (2006).
Karason, A., Love, T.J. & Gudbjornsson, B. A strong heritability of psoriatic arthritis over four generations–the Reykjavik Psoriatic Arthritis Study. Rheumatology (Oxford) 48, 1424–1428 (2009).
Elder, J.T. et al. The genetics of psoriasis. Arch. Dermatol. 130, 216–224 (1994).
Feng, B.J. et al. Multiple loci within the major histocompatibility complex confer risk of psoriasis. PLoS Genet. 5, e1000606 10.1371/journal.pgen.1000606 (2009).
Ho, P.Y. et al. Investigating the role of the HLA-Cw*06 and HLA-DRB1 genes in susceptibility to psoriatic arthritis: comparison with psoriasis and undifferentiated inflammatory arthritis. Ann. Rheum. Dis. 67, 677–682 (2008).
Cargill, M. 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).
Filer, C. et al. Investigation of association of the IL12B and IL23R genes with psoriatic arthritis. Arthritis Rheum. 58, 3705–3709 (2008).
de Cid, R. et al. Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat. Genet. 41, 211–215 (2009).
Huffmeier, U. et al. Deletion of LCE3C and LCE3B genes at PSORS4 does not contribute to susceptibility to psoriatic arthritis in German patients. Ann. Rheum. Dis. 69, 876–878 (2009).
Nair, R.P. et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat. Genet. 41, 199–204 (2009).
Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).
Hüffmeier, U. et al. Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis. J. Invest. Dermatol. 129, 355–358 (2009).
Genetic Analysis of Psoriasis Consortium and the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. advance online publication, doi:10.1038/ng.694 (17 October 2010).
Hunter, C.A. Act1-ivating IL-17 inflammation. Nat. Immunol. 8, 232–234 (2007).
Qian, Y. et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat. Immunol. 8, 247–256 (2007).
Tesmer, L.A., Lundy, S.K., Sarkar, S. & Fox, D.A. Th17 cells in human disease. Immunol. Rev. 223, 87–113 (2008).
Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1240 (2000).
Hoffmann, A. & Baltimore, D. Circuitry of nuclear factor kappaB signaling. Immunol. Rev. 210, 171–186 (2006).
Thomson, W. et al. Rheumatoid arthritis association at 6q23. Nat. Genet. 39, 1431–1433 (2007).
Barton, A. et al. Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13. Nat. Genet. 40, 1156–1159 (2008).
Raychaudhuri, S. et al. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40, 1216–1223 (2008).
Kanamori, M., Kai, C., Hayashizaki, Y. & Suzuki, H. NF-kappaB activator Act1 associates with IL-1/Toll pathway adaptor molecule TRAF6. FEBS. Lett. 532, 241–246 (2002).
Li, Y. & Mach Abecasis, G. 1.0: rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).
Uebe, S. et al. GPFrontend and GPGraphics: Graphical analysis tools for genetic association studies. BMC Bioinformatics 11, 472 (2010).
Huffmeier, U. et al. Characterization of psoriasis susceptibility locus 6 (PSORS6) in patients with early onset psoriasis and evidence for interaction with PSORS1. J. Med. Genet. 46, 736–744 (2009).
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
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–3, Supplementary Tables 1–4 and Supplementary Note. (PDF 819 kb)
Rights and permissions
About this article
Cite this article
Hüffmeier, U., Uebe, S., Ekici, A. et al. Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet 42, 996–999 (2010). https://doi.org/10.1038/ng.688
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.688
This article is cited by
-
Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis
Scientific Reports (2020)
-
The use of leukocytes’ secretome to individually target biological therapy in autoimmune arthritis: a case report
Clinical and Translational Medicine (2019)
-
The Act1 D10N missense variant impairs CD40 signaling in human B-cells
Genes & Immunity (2019)
-
HLA-A*01:01 in MHC is associated with psoriatic arthritis in Chinese Han population
Archives of Dermatological Research (2019)
-
Chronic Mucocutaneous Candidiasis in an Adolescent Boy Due to a Novel Mutation in TRAF3IP2
Journal of Clinical Immunology (2019)