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Extended report
New insight on the Xq28 association with systemic sclerosis
  1. F David Carmona1,
  2. M Carmen Cénit1,
  3. Lina-Marcela Diaz-Gallo1,
  4. Jasper C A Broen2,
  5. Carmen P Simeón3,
  6. Patricia E Carreira4,
  7. José-Luis Callejas-Rubio5,
  8. Vicente Fonollosa3,
  9. Francisco J López-Longo6,
  10. Miguel A González-Gay7,
  11. Nicolas Hunzelmann8,
  12. Gabriela Riemekasten9,
  13. Torsten Witte10,
  14. Alexander Kreuter11,
  15. Jörg H W Distler12,
  16. Rajan Madhok13,
  17. Paul Shiels13,
  18. Jacob M van Laar14,
  19. Annemie J Schuerwegh15,
  20. Madelon C Vonk16,
  21. Alexandre E Voskuyl17,
  22. Carmen Fonseca18,
  23. Christopher P Denton18,
  24. Ariane Herrick19,
  25. Jane Worthington19,
  26. Frank C Arnett20,
  27. Filemon K Tan20,
  28. Shervin Assassi20,
  29. Timothy R D J Radstake2,16,
  30. Maureen D Mayes20,
  31. Javier Martín1,
  32. Spanish Scleroderma Group
  1. 1Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, Granada, Spain
  2. 2Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  3. 3Department of Internal Medicine, Hospital Valle de Hebron, Barcelona, Spain
  4. 4Department of Rheumatology, Hospital 12 de Octubre, Madrid, Spain
  5. 5Department of Internal Medicine, Hospital Clínico Universitario San Cecilio, Granada, Spain
  6. 6Department of Rheumatology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
  7. 7Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain
  8. 8Department of Dermatology, University of Cologne, Cologne, Germany
  9. 9Department of Rheumatology and Clinical Immunology, Charité University Hospital, and German Rheumatism Research Centre, a Leibniz Institute, Berlin, Germany
  10. 10Hannover Medical School, Hannover, Germany
  11. 11Department of Dermatology, Venereology, and Allergology, Ruhr University of Bochum, Bochum, Germany
  12. 12Department of Internal Medicine, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  13. 13Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK
  14. 14Institute of Cellular Medicine, Newcastle University, Newcastle, United Kingdom
  15. 15Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  16. 16Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  17. 17Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  18. 18Centre for Rheumatology, Royal Free and University College Medical School, London, UK
  19. 19Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
  20. 20The University of Texas Health Science Center–Houston, Houston, Texas, USA
  1. Correspondence to Dr F David Carmona, Instituto de Parasitología y Biomedicina López-Neyra. Consejo Superior de Investigaciones Científicas, Parque Tecnológico Ciencias de la Salud. Avenida del Conocimiento s/n, Armilla, Granada 18100, Spain; dcarmona{at} FDC, MCC and LMDG contributed equally. TRDJR, MDM and JM share senior authorship


Objective To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).

Methods We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc.

Results IRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10−3, OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10−4, OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55).

Conclusions Our data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.

  • Autoimmune Diseases
  • Gene Polymorphism
  • Systemic Sclerosis
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