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A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with systemic sclerosis in a large European cohort
  1. Lara Bossini-Castillo1,
  2. Jasper C A Broen2,
  3. Carmen P Simeon3,
  4. Lorenzo Beretta4,
  5. Madelon C Vonk2,
  6. Norberto Ortego-Centeno5,
  7. Gerard Espinosa6,
  8. Patricia Carreira7,
  9. María Teresa Camps8,
  10. Nuria Navarrete9,
  11. María F González-Escribano10,
  12. Esther Vicente-Rabaneda11,
  13. Luis Rodríguez12,
  14. Carlos Tolosa13,
  15. José A Román-Ivorra14,
  16. Inmaculada Gómez-Gracia15,
  17. Francisco J García-Hernández16,
  18. Iván Castellví17,
  19. María Gallego18,
  20. Antonio Fernández-Nebro19,
  21. Rosa García-Portales20,
  22. María Victoria Egurbide21,
  23. Vicente Fonollosa3,
  24. Paloma García de la Peña22,
  25. Ana Pros23,
  26. Miguel A González-Gay24,
  27. Roger Hesselstrand25,
  28. Gabriela Riemekasten26,
  29. Torsten Witte27,
  30. Marieke J H Coenen28,
  31. Bobby P Koeleman29,
  32. Frederic Houssiau30,
  33. Vanessa Smith31,
  34. Filip de Keyser31,
  35. Rene Westhovens32,
  36. Ellen De Langhe32,
  37. Alexandre E Voskuyl33,
  38. Annemie J Schuerwegh34,
  39. Meng May Chee35,
  40. Rajan Madhok35,
  41. Paul Shiels35,
  42. Carmen Fonseca36,
  43. Christopher Denton36,
  44. Kathleen Claes37,
  45. Leonid Padykov38,
  46. Annika Nordin38,
  47. Øyvind Palm39,
  48. Benedicte A Lie40,
  49. Paolo Airó41,
  50. Raffaella Scorza4,
  51. Jacob M van Laar42,
  52. Nicolas Hunzelmann43,
  53. Alexander Kreuter44,
  54. Ariane Herrick45,
  55. Jane Worthington45,
  56. Timothy R D J Radstake2,
  57. Javier Martín1,
  58. Blanca Rueda1,10
  1. 1Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain
  2. 2Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  3. 3Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain
  4. 4Referral Center for Systemic Autoimmune Diseases, University of Milan, Milan, Italy
  5. 5Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain
  6. 6Servicio de Medicina Interna, Hospital Clínico de Barcelona, Barcelona, Spain
  7. 7Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain
  8. 8Servicio de Medicina Interna, Hospital Carlos-Haya, Málaga, Spain
  9. 9Servicio de Medicina Interna, Hospital Virgen de las Nieves, Granada, Spain
  10. 10Servicio de Inmunología, Hospital Virgen del Rocío, Sevilla, Spain
  11. 11Servicio de Reumatología, Hospital de la Princesa, Madrid, Spain
  12. 12Servicio de Reumatología, Hospital Clinico San Carlos, Madrid, Spain
  13. 13Servicio de Medicina Interna, Hospital Parc Tauli, Sabadell, Spain
  14. 14Servicio de Reumatología, Hospital del Doctor Peset aleixandre, Valencia, Spain
  15. 15Servicio de Reumatología, Hospital Reina Sofía, Córdoba, Spain
  16. 16Servicio de Medicina Interna, Hospital Virgen del Rocío, Sevilla, Spain
  17. 17Servicio de Reumatología, Hospital de Sant Pau, Barcelona, Spain
  18. 18Servicio de Medicina Interna, Hospital Central de Asturias, Oviedo, Spain
  19. 19Servicio de Reumatología, Hospital Carlos Haya, Málaga, Spain
  20. 20Servicio de Reumatología, Hospital Virgen de la Victoria, Málaga, Spain
  21. 21Servicio de Medicina Interna, Hospital de Cruces, Barakaldo, Spain
  22. 22Servicio de Reumatología, Hospital Ramón y Cajal, Madrid, Spain
  23. 23Servicio de Reumatología, Hospital Del Mar, Barcelona, Spain
  24. 24Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, Santander, Spain
  25. 25Department of Rheumatology, Lund University Hospital, Lund, Sweden
  26. 26Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
  27. 27Hannover Medical School, Hannover, Germany
  28. 28Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  29. 29Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  30. 30Université Catholique de Louvain (UCL), Brussels, Belgium
  31. 31University of Ghent, Ghent, Belgium
  32. 32University of Leuven (KULeuven), Leuven, Belgium
  33. 33Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  34. 34Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  35. 35University of Glasgow, Glasgow, UK
  36. 36Centre for Rheumatology, Royal Free and University College Medical School, London, UK
  37. 37Department of Genetics, University of Ghent, Ghent, Belgium
  38. 38Karolinska Institute, Stockholm, Sweden
  39. 39Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
  40. 40Institute of Immunology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
  41. 41Servizio di Reumatologia ed Immunologia Clinica Spedali Civili, Brescia, Italy
  42. 42Institute of Cellular Medicine, Newcastle University, Newcastle, UK
  43. 43Department of Dermatology, University of Cologne, Cologne, Germany
  44. 44Ruhr University of Bochum, Bochum, Germany
  45. 45Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  1. Correspondence to Blanca Rueda, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n, 18100-Armilla, Granada, Spain; blarume{at}


Objectives The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features.

Methods A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers.

Results A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively).

Conclusions The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.

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  • JM and BR contributed equally to this work.

  • Funding This work was supported by grants SAF2009-11110, Junta de Andalucía, grants: CTS-4977 and CTS-180 and by RETICS Program, RD08/0075 (RIER) from Instituto de Salud Carlos III (ISCIII). BR was supported by ISCIII (Programa Sara Borrell). TRDJR was funded by the VIDI laureate from the Dutch association of research (NOW) and Dutch arthritis foundation (National Reumafonds). EDL is recipient of an Aspirant fellowship from FWO Vlaanderen (Flanders Research Foundation).

  • Ethical approval Ethical approval was obtained from the Ethics Committee in each hospital involved.

  • Provenance and peer review Not commissioned; externally peer reviewed.