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Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis
  1. LM Diaz-Gallo1,
  2. P Gourh2,
  3. J Broen3,
  4. C Simeon4,
  5. V Fonollosa4,
  6. N Ortego-Centeno5,
  7. S Agarwal2,
  8. MC Vonk3,
  9. M Coenen6,
  10. G Riemekasten7,
  11. N Hunzelmann8,
  12. R Hesselstrand9,
  13. FK Tan2,
  14. JD Reveille2,
  15. S Assassi2,
  16. FJ García-Hernandez10,
  17. P Carreira11,
  18. MT Camps12,
  19. A Fernandez-Nebro13,
  20. P Garcia de la Peña14,
  21. T Nearney15,
  22. D Hilda16,
  23. MA González-Gay17,
  24. P Airo18,
  25. L Beretta19,
  26. R Scorza19,
  27. A Herrick20,
  28. J Worthington20,
  29. A Pros21,
  30. I Gómez-Gracia22,
  31. L Trapiella23,
  32. G Espinosa24,
  33. I Castellvi25,
  34. T Witte26,
  35. F de Keyser27,
  36. M Vanthuyne28,
  37. MD Mayes2,
  38. TRDJ Radstake3,
  39. FC Arnett2,
  40. J Martin1,
  41. B Rueda1
  1. 1Instituto de Parasitología y Biomedicina Lopez-Neyra CSIC, Granada, Spain
  2. 2Department of Internal Medicine, Division of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston Medical School, Houston, USA
  3. 3Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain
  5. 5Servicio de Medicina Interna, Hospital Clinico Universitario, Granada, Spain
  6. 6Departmentof Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  7. 7Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
  8. 8Department of Dermatology, University of Cologne, Germany
  9. 9Department of Rheumatology, Lund University Hospital, Lund, Sweden
  10. 10Servicio de Medicina Interna, Hospital Virgen del Rocio, Sevilla, Spain
  11. 11Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain
  12. 12Servicio de Medicina Interna, Hospital Carlos Haya, Málaga, Spain
  13. 13Servicio de Reumatología, Hospital Carlos Haya, Málaga, Spain
  14. 14Servicio de Reumatología, Hospital Ramon y Cajal, Madrid, Spain
  15. 15University of Texas Medical Branch at Galveston, Galveston, Texas, USA
  16. 16The University of Texas Health Science Center, San Antonio, Texas, USA
  17. 17Servicio de Reumatología, Hospital Marqués de Valdecilla, Santander, Spain
  18. 18Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia, Italy
  19. 19Referral Center for Systemic Autoimmune Diseases, University of Milan, Milan, Italy
  20. 20Rheumatic Diseases Centre, University of Manchester, Salford Royal NHS Foundation Trust, UK
  21. 21Servicio de Reumatología, Hospital del Mar, Barcelona, Spain
  22. 22Servicio de Reumatología, Hospital Reina Sofía, Córdoba, Spain
  23. 23Servicio de Medicina Interna, Hospital Universitario Central de Asturias, Oviedo, Spain
  24. 24Servicio de Medicina Interna, Hospital Clinico, Barcelona, Spain
  25. 25Servicio de Reumatología, Hospital de Sant Pau, Barcelona, Spain
  26. 26Hannover Medical School, Hannover, Germany
  27. 27 Department of Rheumatology, University of Ghent, Belgium
  28. 28Department of Rheumatology, Université Catholique de Louvain, Belgium
  1. Correspondence to Dr Blanca Rueda, Instituto de Parasitología y Biomedicina ‘López-Neyra’, Consejo Superior deInvestigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida delConocimiento s/n, 18100-Armilla, Granada, Spain; blarume{at}


Objective Two functional single nucleotide polymorphisms (SNP) in the PTPN22 gene (rs24746601 and rs33996649) have been associated with autoimmunity. The aim of this study was to investigate the role of the R263Q SNP for the first time and to re-evaluate the role of the R620W SNP in the genetic predisposition to systemic sclerosis (SSc) susceptibility and clinical phenotypes.

Methods 3422 SSc patients (2020 with limited cutaneous SSc and 1208 with diffuse cutaneous SSc) and 3638 healthy controls of Caucasian ancestry from an initial case--control set of Spain and seven additional independent replication cohorts were included in our study. Both rs33996649 and rs2476601 PTPN22 polymorphisms were genotyped by TaqMan allelic discrimination assay. A meta-analysis was performed to test the overall effect of these PTPN22 polymorphisms in SSc.

Results The meta-analysis revealed evidence of association of the rs2476601 T allele with SSc susceptibility (pFDRcorrected=0.03 pooled, OR 1.15, 95% CI 1.03 to 1.28). In addition, the rs2476601 T allele was significantly associated with anticentromere-positive status (pFDRcorrected=0.02 pooled, OR 1.22, 95% CI 1.05 to 1.42). Although the rs33996649 A allele was significantly associated with SSc in the Spanish population (pFDRcorrected=0.04, OR 0.58, 95% CI 0.36 to 0.92), this association was not confirmed in the meta-analysis (p=0.36 pooled, OR 0.89, 95% CI 0.72 to 1.1).

Conclusion The study suggests that the PTPN22 R620W polymorphism influences SSc genetic susceptibility but the novel R263Q genetic variant does not. These data strengthen evidence that the R620W mutation is a common risk factor in autoimmune diseases.

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  • Funding This work was supported by grants SAF2009-11110, Junta de Andalucía, grants CTS-4977 and CTS-180 and by the RETICS Program, RD08/0075 (RIER) from the Instituto de Salud Carlos III (ISCIII). BR was supported by the I3P CSIC programme funded by the ‘Fondo Social Europeo’. LMDG was supported by COLFUTURO and the ‘Ayudas Predoctorales de Formación en Investigación en Salud (PFIS – FI09/00544)’ from the Instituto de Salud Carlos III. The USA contributors were supported by NIH/NIAMS grants P50AR054144, N01-AR-0-2251 and NIH/NCRR 3UL1RR024148.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of each ethics committee of the participating hospitals.

  • Provenance and peer review Not commissioned; externally peer reviewed