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Evidence for caveolin-1 as a new susceptibility gene regulating tissue fibrosis in systemic sclerosis
  1. Mirko Manetti1,2,
  2. Yannick Allanore3,4,
  3. Mohamad Saad5,
  4. Cinzia Fatini6,
  5. Vanessa Cohignac3,4,
  6. Serena Guiducci2,
  7. Eloisa Romano2,
  8. Paolo Airó7,
  9. Paola Caramaschi8,
  10. Ilaria Tinazzi8,
  11. Valeria Riccieri9,
  12. Alessandra Della Rossa10,
  13. Rosanna Abbate6,
  14. Roberto Caporali11,
  15. Giovanna Cuomo12,
  16. Guido Valesini9,
  17. Philippe Dieudé13,
  18. Eric Hachulla14,
  19. Jean-Luc Cracowski15,
  20. Kiet Tiev16,
  21. Luc Letenneur17,
  22. Philippe Amouyel18,
  23. Jean-Charles Lambert18,
  24. Gilles Chiocchia3,4,
  25. Maria Martinez5,
  26. Lidia Ibba-Manneschi1,
  27. Marco Matucci-Cerinic2
  1. 1Department of Anatomy, Histology and Forensic Medicine, University of Florence, Florence, Italy
  2. 2Department of Biomedicine, Division of Rheumatology, AOUC and Excellence Centre for Research, Transfer and High Education DENOthe, University of Florence, Florence, Italy
  3. 3Université Paris Descartes, Rhumatologie A, Hôpital Cochin, APHP, Paris, France
  4. 4INSERM U1016, Institut Cochin, Paris, France
  5. 5INSERM UMR1043, CPTP, CHU Purpan, Université Paul Sabatier, Toulouse, France
  6. 6Department of Medical and Surgical Critical Care, Thrombosis Centre, University of Florence, Florence, Italy
  7. 7Rheumatology and Clinical Immunology, Spedali Civili, Brescia, Italy
  8. 8Rheumatology Unit, University of Verona, Verona, Italy
  9. 9Division of Rheumatology, Department of Internal Medicine and Medical Specialities, University ‘Sapienza’, Rome, Italy
  10. 10Division of Rheumatology, University of Pisa, Pisa, Italy
  11. 11Division of Rheumatology, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
  12. 12Department of Clinical and Experimental Medicine, Rheumatology Unit, Second University of Naples, Naples, Italy
  13. 13Université Paris Diderot, Rhumatologie, INSERM U699, Hôpital Bichat Claude-Bernard, Paris, France
  14. 14Université Lille II, Médecine Interne, CHU Lille, France
  15. 15INSERM, CIC3, CHU Grenoble, France
  16. 16Université Pierre et Marie Curie, Hôpital Saint Antoine, Paris, France
  17. 17INSERM U897, Université Victor Segalen, Bordeaux, France
  18. 18INSERM U744, Institut Pasteur de Lille, Université de Lille Nord, Lille, France
  1. Correspondence to Dr Mirko Manetti, Department of Anatomy, Histology and Forensic Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; mirkomanetti{at}


Objective Caveolin-1 (CAV1) is an inhibitor of tissue fibrosis and has been implicated in the pathogenesis of systemic sclerosis (SSc). The aim of the study was to analyse the possible association of CAV1 gene single nucleotide polymorphisms (SNP) with SSc.

Methods A total population of 3974 individuals (1355 SSc patients, 2619 controls) was studied. Genotype data for 23 SNP spanning the CAV1–CAV2 gene locus were obtained from a genome-wide scan conducted in a French population (564 SSc patients, 1776 controls). Three CAV1 SNP (rs926198, rs959173, rs9920) displaying the most significant associations with SSc and/or clinical phenotypes were then genotyped in an Italian population (791 SSc patients, 843 controls). CAV1 protein expression in skin biopsies was investigated by immunohistochemistry and western blotting.

Results In the French population, the CAV1 rs959173 C minor allele showed a significant protective association with susceptibility to SSc (OR 0.71, 95% CI 0.59 to 0.86, padjusted=0.009), and with the subset of patients with limited cutaneous SSc (OR 0.71, 95% CI 0.56 to 0.89, padjusted=0.018). The association was replicated in the Italian population and strengthened in the combined populations through Cochran–Mantel–Haenszel meta-analysis (SSc: pooled OR 0.81, 95% CI 0.71 to 0.92, p=0.0018; limited cutaneous SSc: pooled OR 0.80, 95% CI 0.69 to 0.93, p=0.0053). Genotype/protein expression correlations revealed that the rs959173 C protective allele was associated with increased CAV1 protein expression.

Conclusions These results add CAV1 to the list of SSc susceptibility genes and provide further evidence for the contribution of this pathway in the fibrotic process that characterises SSc pathogenesis.

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  • Funding This study was funded by Agence Nationale pour la Recherche (project ANR-08-GENO-016-1) and supported by research grants from SERVIER research group, Sanofi-Aventis, Association des Sclérodermies de France and the University of Florence (progetti di ricerca di ateneo, ex60% to LIM and MMC).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The study was approved by the local institutional review boards. The study complied with the principles of the Declaration of Helsinki.

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

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