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Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

A Corrigendum to this article was published on 27 April 2011

This article has been updated


Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22–23, rs2056626, P = 2.09 × 10−7 in the discovery samples, P = 3.39 × 10−9 in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 × 10−18), IRF5 (P = 1.86 × 10−13) and STAT4 (P = 3.37 × 10−9) gene regions as SSc genetic risk factors.

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Figure 1: Manhattan plot of the GWAS of the discovery cohort comprising 2,346 SSc cases and 5,193 healthy controls.
Figure 2

Change history

  • 16 April 2010

    In the version of this article initially published online, the name of author Annemie J. Schuerwegh was misspelled. The error has been corrected for the print, PDF, and HTML versions of this article.

  • 23 March 2011

    In the version of this article initially published, incorrect affiliations were published for Lorenzo Beretta and Raffaella Scorza. The correct affiliation for Lorenzo Beretta and Raffaella Scorza is "Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan". The error has been corrected in the HTML and PDF versions of the article.


  1. Gabrielli, A., Avvedimento, E.V. & Krieg, T. Scleroderma. N. Engl. J. Med. 360, 1989–2003 (2009).

    Article  CAS  Google Scholar 

  2. Jimenez, S.A. & Derk, C.T. Following the molecular pathways toward an understanding of the pathogenesis of systemic sclerosis. Ann. Intern. Med. 140, 37–50 (2004).

    Article  CAS  Google Scholar 

  3. Agarwal, S.K., Tan, F.K. & Arnett, F.C. Genetics and genomic studies in scleroderma (systemic sclerosis). Rheum. Dis. Clin. North Am. 34, 17–40 (2008).

    Article  Google Scholar 

  4. Arnett, F.C. et al. Major Histocompatibility Complex (MHC) class II alleles, haplotypes, and epitopes which confer susceptibility or protection in the fibrosing autoimmune disease systemic sclerosis: analyses in 1300 Caucasian, African-American and Hispanic cases and 1000 controls. Ann. Rheum. Dis. published online (12 July 2009).

  5. Rueda, B. et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum. Mol. Genet. 18, 2071–2077 (2009).

    Article  CAS  Google Scholar 

  6. Tsuchiya, N. et al. Association of STAT4 polymorphism with systemic sclerosis in a Japanese population. Ann. Rheum. Dis. 68, 1375–1376 (2009).

    Article  CAS  Google Scholar 

  7. Ito, I. et al. Association of a functional polymorphism in the IRF5 region with systemic sclerosis in a Japanese population. Arthritis Rheum. 60, 1845–1850 (2009).

    Article  CAS  Google Scholar 

  8. Dieudé, P. et al. Association between the IRF5 rs2004640 functional polymorphism and systemic sclerosis: a new perspective for pulmonary fibrosis. Arthritis Rheum. 60, 225–233 (2009).

    Article  Google Scholar 

  9. Gregersen, P.K. & Olsson, L.M. Recent advances in the genetics of autoimmune disease. Annu. Rev. Immunol. 27, 363–391 (2009).

    Article  CAS  Google Scholar 

  10. Hunter, D.J. et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874 (2007).

    Article  CAS  Google Scholar 

  11. Yeager, M. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645–649 (2007).

    Article  CAS  Google Scholar 

  12. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    Article  CAS  Google Scholar 

  13. Krawczak, M. et al. PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community Genet. 9, 55–61 (2006).

    PubMed  Google Scholar 

  14. Wellcome Trust Case-Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  15. Call, M.E. & Wucherpfennig, K.W. Molecular mechanisms for the assembly of the T cell receptor-CD3 complex. Mol. Immunol. 40, 1295–1305 (2004).

    Article  CAS  Google Scholar 

  16. Krishnan, S. et al. Increased caspase-3 expression and activity contribute to reduced CD3zeta expression in systemic lupus erythematosus T cells. J. Immunol. 175, 3417–3423 (2005).

    Article  CAS  Google Scholar 

  17. Krishnan, S. et al. Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3ζ expression. Blood 97, 3851–3859 (2001).

    Article  CAS  Google Scholar 

  18. Krishnan, S., Warke, V.G., Nambiar, M.P., Tsokos, G.C. & Farber, D.L. The FcR gamma subunit and Syk kinase replace the CD3 zeta-chain and ZAP-70 kinase in the TCR signaling complex of human effector CD4 T cells. J. Immunol. 170, 4189–4195 (2003).

    Article  CAS  Google Scholar 

  19. Gorman, C.L. et al. Polymorphisms in the CD3Z gene influence TCRzeta expression in systemic lupus erythematosus patients and healthy controls. J. Immunol. 180, 1060–1070 (2008).

    Article  CAS  Google Scholar 

  20. Warchol, T. et al. The CD3Z 844 T>A polymorphism within the 3′-UTR of CD3Z confers increased risk of incidence of systemic lupus erythematosus. Tissue Antigens 74, 68–72 (2009).

    Article  CAS  Google Scholar 

  21. Gourh, P. et al. Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis. Arthritis Rheum. 54, 3945–3953 (2006).

    Article  CAS  Google Scholar 

  22. Anonymous. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 23, 581–590 (1980).

  23. 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).

    Article  CAS  Google Scholar 

  24. Tian, C. et al. European population genetic substructure: further definition of ancestry informative markers for distinguishing among diverse European ethnic groups. Mol. Med. 15, 371–383 (2009).

    Article  CAS  Google Scholar 

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This work was supported by the following grants: T.R.D.J.R. was funded by the VIDI laureate from the Dutch Association of Research (NWO) and Dutch Arthritis Foundation (National Reumafonds). J.M. was funded by GEN-FER from the Spanish Society of Rheumatology, SAF2009-11110 from the Spanish Ministry of Science, CTS-4977 from Junta de Andalucía, Spain and in part by Redes Temáticas de Investigación Cooperativa Sanitaria Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII), Spain (J.M.). R.B. is supported by the I3P Consejo Superior de Investigaciones Científicas program funded by the 'Fondo Social Europeo'. B.Z.A. is supported by the Netherlands Organization for Health Research and Development (ZonMW grant 016.096.121). B.K. is supported by the Dutch Diabetes Research Foundation (grant 2008.40.001) and the Dutch Arthritis Foundation (Reumafonds, grant NR 09-1-408). Genotyping of the Dutch control samples was sponsored by US National Insitutes of Mental Health funding, R01 MH078075 (R.O.A.). The German controls were from the PopGen biobank (to B.K.). The PopGen project received infrastructure support through the German Research Foundation excellence cluster 'Inflammation at Interfaces'. The US analyses were supported by the US National Institutes of Health and National Institute of Arthritis and Musculoskeletal Diseases (NIH-NIAMS) R01 AR055258, Two-Stage Genome Wide Association Study in Systemic Sclerosis, (M.D.M.) and by the NIH-NIAMS Center of Research Translation (CORT) in SSc (P50AR054144) (F.C.A.), the NIH-NIAMS SSc Family Registry and DNA Repository (N01-AR-0-2251) (M.D.M.), University of Texas Health Science Center-Houston Center for Clinical and Translational Sciences (Houston Clinical and Translational Science Awards Program) (NIH-National Center for Research Resources 3UL1RR024148) (F.C.A.), NIH-NIAMS K08 Award (K08AR054404) (S.K.A.), SSc Foundation New Investigator Award (S.K.A.).

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Study Design: T.R.D.J.R., O.G., B.R., J.-E.M., B.P.C.K., F.C.A., J.M., M.D.M.

Collection of data: T.R.D.J.R., M.J.C., M.C.V., A.E.V., A.J.S., J.C.B., B.A.L., A.-M.H.-V., R.A.O., G.R., N.H., C.P.S., N.O.-C., M.A.G.-G., M.F.G.-E., P.A., J.v.L., A.H., J.W., R.H., V.S., F.d.K., F.H., M.M.C., R.M., P.S., R.W., A.K., H.K., E.d.B., T.W., L.P., L.K., L.B., R.S., J.V., M.H., P.G., J.L.N., F.M.W., L.H., P.C., S.A.

Interpretation and analysis of results: T.R.D.J.R., O.G., B.R., J.-E.M., B.Z.A., R.P.-M., J.Y., Y.H., S.-F.W., R.v.'t.S., P.G., A.T.L., C.I.A., S.K.A., B.P.C.K., J.M., M.D.M., A.I., P.C., S.A., P.K.G.

Critical reading of manuscript: T.R.D.J.R., O.G., B.R., J.-E.M., B.Z.A., J.Y., M.J.C., M.C.V., A.E.V., A.J.S., J.C.B., P.L.C.M.v.R., R.v.S., B.A.L., A.-M.H.-V., G.R., N.H., C.P.S., N.O.-C., M.A.G.-G., M.F.G.-E., P.A., J.v.L., A.H., J.W., R.H., V.S., F.d.K., F.H., M.M.C., R.M., P.S., R.W., A.K., H.K., E.d.B., T.W., L.P., L.B., R.S., J.V., M.H., P.G., C.I.A., J.L.N., F.M.W., L.H., S.K.A., P.G., F.K.T., B.P.C.K., F.C.A., J.M., M.D.M., P.K.G.

Project conception: T.R.D.J.R., B.P.C.K., F.C.A., J.M., M.D.M.

Corresponding authors

Correspondence to Timothy R D J Radstake or Maureen D Mayes.

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The authors declare no competing financial interests.

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A full list of members is provided in the Supplementary Note.

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Radstake, T., Gorlova, O., Rueda, B. et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42, 426–429 (2010).

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