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NLRP1 influences the systemic sclerosis phenotype: a new clue for the contribution of innate immunity in systemic sclerosis-related fibrosing alveolitis pathogenesis
  1. P Dieudé1,
  2. M Guedj2,
  3. J Wipff3,4,
  4. B Ruiz3,
  5. G Riemekasten5,
  6. P Airo6,
  7. I Melchers7,
  8. E Hachulla8,
  9. M Matucci Cerinic9,
  10. E Diot10,
  11. N Hunzelmann11,
  12. P Caramaschi12,
  13. J Sibilia13,
  14. K Tiev14,
  15. L Mouthon15,
  16. V Riccieri16,
  17. J L Cracowski17,
  18. P H Carpentier18,
  19. J Distler19,
  20. Z Amoura20,
  21. I Tarner21,
  22. J Avouac3,4,
  23. O Meyer1,
  24. A Kahan4,
  25. C Boileau3,22,
  26. Y Allanore3,4
  1. 1Department of Rheumatology, Paris Diderot University, INSERM U699, Bichat Claude Bernard Hospital, APHP, Paris, France
  2. 2Laboratoire Statistique et Génome, UMR CNRS-8071/INRA-1152/Université d'Evry Val d'Essonne, Évry, France
  3. 3Paris Descartes University, INSERM U781, Necker Hospital, Paris, France
  4. 4Department of Rheumatology A, Paris Descartes University, INSERM U1016, Cochin Hospital, Paris, France
  5. 5Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
  6. 6Rheumatology and Clinical Immunology, Spedali Civili, Brescia, Italy
  7. 7Clinical Research Unit for Rheumatology, University Medical Center, Freiburg, Germany
  8. 8Internal Medecine Department, Lille II University, Lille, France
  9. 9Department of Biomedicine, Section of Rheumatology, Florence, Italy
  10. 10INSERM U618, IFR 135, CHU Bretonneau, Tours, France
  11. 11Department of Dermatology, University of Cologne, Köln, Germany
  12. 12Department of Clinical and Experimental Medicine – Rheumatology Unit, University of Verona, Verona, Italy
  13. 13Université Louis Pasteur, Service de Rhumatologie, Hôpital Hautepierre, Strasbourg, France
  14. 14Pierre et Marie Curie University, Saint-Antoine Hospital, APHP, Paris, France
  15. 15Department of Internal Medicine, Paris Descartes University, Cochin Hospital, APHP, Paris, France
  16. 16Division of Rheumatology, Department of Medical Clinic and Therapy, University of ‘Sapienza’, Rome, Italy
  17. 17INSERM CIC3, CHU Grenoble, Grenoble, France
  18. 18Clinique universitaire de Médecine Vasculaire, Pôle pluridisciplinaire de Médecine, CHU Grenoble, Grenoble, France
  19. 19Department for Internal Medicine 3 and Institute for Clinical Immunology, Friedrich-Alexander University, Erlangen-Nuremberg, Germany
  20. 20Internal Medecine Department 2, Paris 6 University, Pitié-Salpêtrière Hospital, APHP, Paris, France
  21. 21Department for Rheumatology and Clinical Immunology, University of Giessen, Kerckhoff Clinic, Bad Nauheim, Germany
  22. 22Laboratoire de Biochimie Hormonale et Génétique, Saint Quentin Yvelines University, Ambroise Paré Hospital, APHP, Boulogne, France
  1. Correspondence to Dr Philippe Dieudé, Service de Rhumatologie, Paris Diderot University, INSERM U699, Hôpital Bichat Claude Bernard, 46 rue Henri Huchard, 75018 Paris, France; philippe.dieude{at}


Background Recent evidence has highlighted a potential role of interleukin 1β (IL-1β) in systemic sclerosis (SSc). NLRP1 provides a scaffold for the assembly of the inflammasome that promotes the processing and maturation of pro-IL-1β. In addition, NLRP1 variants were found to confer susceptibility to autoimmune disorders.

Objective To study a possible association of the NLRP1 rs6502867, rs2670660 and rs8182352, rs12150220 and rs4790797 with SSc in the European Caucasian population.

Methods NLRP1 single nucleotide polymorphisms were genotyped in 3227 individuals comprising a discovery set (870 SSc patients and 962 controls) and a replication set including individuals from Germany (532 SSc patients and 324 controls) and Italy (527 SSc patients and 301 controls), all individuals being of European Caucasian origin.

Results Conditional analyses revealed a significant association for the NLRP1 rs8182352 variant with both anti-topoisomerase-positive and SSc-related fibrosing alveolitis (FA) subsets under an additive model: p=0.0042, OR 1.23 (95% CI 1.07 to 1.41) and p=0.0065 OR 1.19 (95% CI 1.05 to 1.36), respectively. Logistic regression analysis showed an additive effect of IRF5 rs2004640, STAT4 rs7574865 and NLRP1 rs8182352 risk alleles on SSc-related FA.

Conclusions Our results establish NLRP1 as a new genetic susceptibility factor for SSc-related pulmonary fibrosis and anti-topoisomerase-positive SSc phenotypes. This provides new insights into the pathogenesis of SSc, underlining the potential role of innate immunity in particular in the FA-positive SSc subphenotype, which represents a severe subset of the disease.

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  • Funding ANR (grant R070994KS), SFR, ASF, GFRS, INSERM. The German Network for Systemic Sclerosis was funded by the German Federal Ministry for Education and Research (grant nos 01 GM 0310 and 01 GM 0634 to IM, GR, NH and IT).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Comité de Protection des Personnes of Cochin Hospital, Paris, France.

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