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TGFβ receptor gene variants in systemic sclerosis-related pulmonary arterial hypertension: results from a multicentre EUSTAR study of European Caucasian patients
  1. Eugénie Koumakis1,2,
  2. Julien Wipff1,2,
  3. Philippe Dieudé3,
  4. Barbara Ruiz1,
  5. Matthieu Bouaziz4,
  6. Lucile Revillod1,
  7. Mickaël Guedj4,
  8. Jörg H W Distler5,
  9. Marco Matucci-Cerinic6,
  10. Marc Humbert7–9,
  11. Gabriella Riemekasten10,11,
  12. Paolo Airo12,
  13. Inga Melchers13,
  14. Eric Hachulla14,
  15. Daniele Cusi15,16,
  16. H- Erich Wichmann17,18,19,
  17. Nicolas Hunzelmann20,
  18. Kiet Tiev21,
  19. Paola Caramaschi22,
  20. Elisabeth Diot23,
  21. Otylia Kowal-Bielecka24,
  22. Giovanna Cuomo25,
  23. Ulrich Walker26,
  24. László Czirják27,
  25. Nemanja Damjanov28,
  26. Sara Lupoli16,
  27. Costanza Conti29,
  28. Martina Müller-Nurasyid30,31,32,
  29. Ulf Müller-Ladner33,
  30. Valeria Riccieri34,
  31. Jean-Luc Cracowski35,
  32. Franco Cozzi36,
  33. Vasiliki Kalliopi Bournia37,
  34. P Vlachoyiannopoulos37,
  35. Gilles Chiocchia1,
  36. Catherine Boileau38,
  37. Yannick Allanore1,2
  1. 1Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France
  2. 2Rheumatology A Department, Paris Descartes University, Cochin Hospital, APHP, Paris, France
  3. 3Department of Rhumatologie, Université Paris 7, INSERM U699, Hôpital Bichat, Paris, France
  4. 4UMR CNRS-8071/INRA-1152, Université d'Evry Val d'Essonne, Evry, France
  5. 5Department for Internal Medicine 3, Institute for Clinical Immunology Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
  6. 6Department of Biomedicine & Division of Rheumatology AOUC, Department of Rheumatology AVC, Department of Medicine & Denothe Centre, University of Florence, Florence, Italy
  7. 7Université Paris-Sud, Le Kremlin-Bicêtre, France
  8. 8AP-HP Hôpital Antoine Béclère, Clamart, France
  9. 9INSERM U999, Centre Chirurgical Marie-Lannelongue, Le Plessis-Robinson, France
  10. 10Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany
  11. 11German Rheumatism Research Centre, a Leibniz Institute, Berlin, Germany
  12. 12Department of Rheumatology and Clinical Immunology, Spedali Civili, Brescia, Italy
  13. 13Department of Clinical Research Unit for Rheumatology, University Medical Center, Freiburg, Germany
  14. 14Department of Médecine Interne, Université Lille II, Lille, France
  15. 15University of Milano, Department of Medicine, Surgery, and Dentistry, San Paolo School of Medicine, Milan, Italy
  16. 16Genomics and Bioinformatics Platform, Fondazione Filarete, Milan, Italy
  17. 17Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  18. 18Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
  19. 19Klinikum Grosshadern, Munich, Germany
  20. 20Department of Dermatology, University of Cologne, Cologne, Germany
  21. 21Université Pierre et Marie Curie, Service de Médecine Interne, Hôpital Saint Antoine, Paris, France
  22. 22Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Verona, Verona, Italy
  23. 23INSERM U618, IFR 135, CHU Bretonneau, Tours, France
  24. 24Department of Rheumatology and Internal Medicine, Medical University of Bialystok, Bialystok, Poland
  25. 25Department of Clinical and Experimental Medicine, Rheumatology Unit, Second University of Naples, Naples, Italy
  26. 26Department of Rheumatology, Basel University, Basel, Switzerland
  27. 27Department of Immunology and Rheumatology, University of Pécs, Pécs, Hungary
  28. 28Institute of Rheumatology, School of Medicine, University of Belgrade, Belgrade, Serbia
  29. 29Kos Genetic SRL, Milan, Italy
  30. 30Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
  31. 31Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology and Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
  32. 32Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany
  33. 33Department of Rheumatology and Clinical Immunology, University of Giessen, Kerckhoff-Klinik, Bad Nauheim, Germany
  34. 34Department of Medical Clinic and Therapy, Division of Rheumatology, University ‘Sapienza’ of Rome, Rome, Italy
  35. 35INSERM CIC3, CHU Grenoble, Grenoble, France
  36. 36Cattedra di Reumatologia, Dip. Medicina Clinica e Sperimentale, Policlinico – Universita’ di Padova, Padua, Italy
  37. 37Department of Pathophysiology, Medical School, University of Athens, Athens, Greece
  38. 38Department of Biochemistry, Genetic and Hormonology, Ambroise Paré Hospital, Boulogne and INSERM U698, Bichat Hospital, Paris, France
  1. Correspondence to Professor Yannick Allanore, Service de Rhumatologie A, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, Paris 75014, France; yannick.allanore{at}


Introduction Systemic sclerosis (SSc)-related pulmonary arterial hypertension (PAH) has emerged as a major mortality prognostic factor. Mutations of transforming growth factor beta (TGFβ) receptor genes strongly contribute to idiopathic and familial PAH.

Objective To explore the genetic bases of SSc–PAH, we combined direct sequencing and genotyping of candidate genes encoding TGFβ receptor family members.

Materials and methods TGFβ receptor genes, BMPR2, ALK1, TGFR2 and ENG, were sequenced in 10 SSc–PAH patients, nine SSc and seven controls. In addition, 22 single-nucleotide polymorphisms (SNP) of these four candidate genes were tested for association in a first set of 824 French Caucasian SSc patients (including 54 SSc–PAH) and 939 controls. The replication set consisted of 1516 European SSc (including 219 SSc–PAH) and 3129 controls from the European League Against Rheumatism Scleroderma Trials and Research group network.

Results No mutation was identified by direct sequencing. However, two repertoried SNP, ENG rs35400405 and ALK1 rs2277382, were found in SSc–PAH patients only. The genotyping of 22 SNP including the latter showed that only rs2277382 was associated with SSc–PAH (p=0.0066, OR 2.13, 95% CI 1.24 to 3.65). Nevertheless, this was not replicated with the following result in combined analysis: p=0.123, OR 0.79, 95% CI 0.59 to 1.07.

Conclusions This study demonstrates the lack of association between these TGFβ receptor gene polymorphisms and SSc–PAH using both sequencing and genotyping methods.

  • Systemic Sclerosis
  • Gene Polymorphism
  • Autoimmune Diseases

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