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Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility
  1. Lina-Marcela Diaz-Gallo1,
  2. Carmen P Simeon2,
  3. Jasper C Broen3,
  4. Norberto Ortego-Centeno4,
  5. Lorenzo Beretta5,
  6. Madelon C Vonk3,
  7. Patricia E Carreira6,
  8. Sofia Vargas1,
  9. José Andrés Román-Ivorra7,
  10. Miguel A González-Gay8,
  11. Carlos Tolosa9,
  12. Francisco Javier López-Longo10,
  13. Gerard Espinosa11,
  14. Esther F Vicente12,
  15. Roger Hesselstrand13,
  16. Gabriela Riemekasten14,
  17. Torsten Witte15,
  18. Jörg H W Distler16,
  19. Alexandre E Voskuyl17,
  20. Annemie J Schuerwegh18,
  21. Paul G Shiels19,
  22. Annika Nordin20,
  23. Leonid Padyukov20,
  24. Anna-Maria Hoffmann-Vold21,
  25. Raffaella Scorza5,
  26. Claudio Lunardi22,
  27. Paolo Airo23,
  28. Jacob M van Laar24,
  29. Nicolas Hunzelmann25,
  30. Birgit S Gathof26,
  31. Alexander Kreuter27,
  32. Ariane Herrick28,
  33. Jane Worthington28,
  34. Christopher P Denton29,
  35. Xiaodong Zhou30,
  36. Frank C Arnett30,
  37. Carmen Fonseca29,
  38. Bobby PC Koeleman31,
  39. Shervin Assasi30,
  40. Timothy R D J Radstake32,
  41. Maureen D Mayes30,
  42. Javier Martín1,
  43. The Spanish Scleroderma Group
  1. 1Cellular Biology and Immunology Department, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain
  2. 2Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain
  3. 3Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  4. 4Department of Internal Medicine, Hospital Clínico Universitario San Cecilio, Granada, Spain
  5. 5Department of Allergy, Clinical Immunology and Rheumatology, IRCCS Fondazione Policlinico-Mangiagalli-Regina Elena & University of Milan, Milan, Italy
  6. 6Department of Rheumatology, Hospital Universitario 12 de Octubre, Madrid, Spain
  7. 7Department of Rheumatology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
  8. 8Department of Rheumatology, Hospital Marqués de Valdecilla, IFIMAV, Santander, Spain
  9. 9Department of Internal Medicine, Hospital Parc Tauli, Sabadell, Spain
  10. 10Department of Rheumatology, Hospital General Universitario Gregorio Marañon, Madrid, Spain
  11. 11Department of Systemic Autoimmune Diseases, Hospital Clinic de Barcelona, Barcelona, Spain
  12. 12Department of Rheumatology, Hospital Universitario La Princesa, Madrid, Spain
  13. 13Department of Rheumatology, Lund University Hospital, Lund, Sweden
  14. 14Department of Rheumatology and Clinical Immunology, Charité Universitátsmedizin and German Rheumatism Research Centre, a Leibniz institute. Berlin, Germany
  15. 15Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany
  16. 16Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  17. 17Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  18. 18Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  19. 19Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland
  20. 20Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  21. 21Department of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway
  22. 22Department of Medicine, Università degli Studi di Verona, Verona, Italy
  23. 23UO Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, Italy
  24. 24Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle, UK
  25. 25Department of Dermatology, University of Cologne, Cologne, Germany
  26. 26Division of Transfusion Medicine, University Hospital of Cologne, Cologne, Germany
  27. 27Department of Dermatology, Allergology, and Venereology, Ruhr University of Bochum, Bochum, Germany
  28. 28Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  29. 29Centre for Rheumatology, Royal Free and University College Medical School, London, UK
  30. 30Department of Rheumatology and Clinical Immunogenetics, The University of Texas Health Science Center at Houston, Houston, Texas, USA
  31. 31Section Complex Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  32. 32Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  1. Correspondence to Lina-Marcela Diaz-Gallo, Cellular Biology and Immunology Department, Instituto de Parasitología y Biomedicina López-Neyra (IPBLN-CSIC), Parque Tecnológico Ciencias de la Salud, Avenida del Conocimiento s/n 18100-Armilla, Granada 18100, Spain; lina.diaz{at}


Objective The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc).

Patients and methods The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays.

Results We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively).

Conclusions These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.

  • Systemic Sclerosis
  • Gene Polymorphism
  • Autoimmune Diseases

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