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Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development
  1. J C A Broen1,
  2. P Gourh2,
  3. M C Vonk1,
  4. L Beretta3,
  5. F Niederer4,
  6. B Rueda5,
  7. L Geurts-van Bon1,
  8. C Brouwer1,
  9. R Hesselstrand6,
  10. A Herrick7,
  11. J Worthington7,
  12. N Hunzelman8,
  13. Denton C Fonseca9,
  14. G Riemekasten10,
  15. H Kiener11,
  16. R Scorza3,
  17. C P Simeon12,
  18. V Fonollosa12,
  19. (for the Spanish Systemic Sclerosis group),
  20. P Carreira13,
  21. N Ortego-Centeno14,
  22. M A Gonzalez-Gay15,
  23. P Airo'16,
  24. M J H Coenen17,
  25. M Mayes2,
  26. D Kyburz4,
  27. F C Arnett2,
  28. J Martin5,
  29. T R D J Radstake1
  1. 1Department of Rheumatology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  2. 2Department of Internal Medicine, Division of Rheumatology and Clinical Immunogenetics, University of Texas Health Science Center at Houston (UTHSC-H), Houston, Texas, USA
  3. 3Referral Center for Systemic Autoimmune Diseases, University of Milan, Milan, Italy
  4. 4Division of Rheumatology, University Hospital Zurich, Zürich, Switzerland
  5. 5Instituto de Parasitología y Biomedicina, CSIC, Granada, Spain
  6. 6Department of Rheumatology, Lund University Hospital, Lund, Sweden
  7. 7Rheumatic Diseases Centre, University of Manchester, Salford Royal NHS Foundation Trust, Manchester, UK
  8. 8Department of Dermatology, University of Cologne, Cologne, Germany
  9. 9Centre for Rheumatology, Royal Free and University College Medical School, London, UK
  10. 10Department of Rheumatology and Clinical Immunology, Charité University Hospital and German Rheumatism Research Centre, a Leibniz institute, Berlin, Germany
  11. 11Department of Internal Medicine, Division of Rheumatology, University of Vienna, Vienna, Austria
  12. 12Servicio de Medicina Interna, Hospital Vall d'Hebron, Barcelona, Spain
  13. 13Servicio de Reumatologia, Hospital 12 de Octubre, Madrid, Spain
  14. 14Servicio de Medicina Interna, Hospital Clinico Universitario, Granada, Spain
  15. 15Servicio de Reumatologia, Hospital Marques de Valdecillas, Santander, Spain
  16. 16Servizio di Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, Italy
  17. 17Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Abstract

Aim Pre-B cell colony-enhancing factor (PBEF) is intricately involved in inflammation and fibrosis, functional polymorphisms of PBEF have been previously shown to influence PBEF expression and pulmonary damage. Systemic sclerosis (SSc) is a disease in which inflammation, fibrosis and pulmonary deterioration are prominent hallmarks. Therefore the authors here investigate the role of the PBEF -1001T>G and PBEF -1543C>T polymorphisms in the genetic predisposition to SSc susceptibility and pulmonary involvement.

Patients and methods The authors genotyped DNA from 2737 SSc patients and 1913 matched healthy controls, both from eight different ethnic populations. Genotyping was performed using custom Taqman 5' allelic discrimination assays. In addition, PBEF serum expression levels were measured by ELISA and correlated with genotypes.

Results In two separate populations and in a meta-analysis, the combined PBEF -1543CC -1001TT genotype, hence carrying no minor alleles, was found associated with SSc susceptibility (p=0.009 OR 1.20 (95% CI 1.05 to 1.37)). In addition, these subjects showed an increased decline in forced vital capacity over 15 years follow-up (p=0.02) (HR 1.64, 95% CI 1.02 to 2.64) and a higher PBEF serum concentration (p<0.01), compared to carriers of minor alleles. On the other hand, patients with genotype PBEF -1001TT were at lower risk for PAH development within 15 years of disease onset compared to the carriers with genotypes PBEF -1001GG and PBEF -1001TG (p<0.001) (HR 3.29, 95% CI 1.52 to 7.12).

Conclusions This data identify PBEF as a novel candidate gene that influences SSc susceptibility, pulmonary function and the development of PAH.

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