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This article is part of the supplement: 5th European Workshop on Immune-Mediated Inflammatory Diseases

Open Access Poster presentation

Variants of PBEF predispose to systemic sclerosis and pulmonary arterial hypertension development

JCA Broen1*, P Gourh2, M C Vonk1, L Beretta3, F Niederer4, B Rueda5, L Geurts-van Bon1, C Brouwer1, R Hesselstrand6, A Herrick7, J Worthington7, N Hunzelman8, C Denton9, C Fonseca9, G Riemekasten10, H Kiener11, R Scorza3, C P Simeon12, V Fonollosa12, P Carreira13, N Ortego-Centeno14, M A Gonzalez-Gay15, P Airò16, MJH Coenen17, M Mayes2, D Kyburz4, F C Arnett2, J Martin5 and TRDJ Radstake1

  • * Corresponding author: JCA Broen

  • † Equal contributors

Author Affiliations

1 Dept. of Rheumatology, Radboud University Nijmegen Medical Center, The Netherlands

2 Division of Rheumatology and Clinical Immunogenetics, Dept. of Internal Medicine, University of Texas Health Science Center at Houston (UTHSC-H), Houston, TX, USA

3 Referral Center for Systemic Autoimmune Diseases, University of Milan, Italy

4 University Hospital Zurich Div. of Rheumatology Zurich, Switzerland

5 Instituto de Parasitología y Biomedicina, CSIC, Granada, Spain

6 Dept. of Rheumatology, Lund University Hospital, Lund, Sweden

7 Rheumatic Diseases Centre, University of Manchester, Salford Royal NHS Foundation Trust, UK

8 Dept. of Dermatology, University of Cologne, Germany

9 Centre for Rheumatology, Royal Free and University College Medical School, London, UK

10 Dept.of Rheumatology and Clinical Immunology, Charité University Hospital and German Rheumatism Research Centre, a Leibniz institute

11 Dept. of Internal Medicine, division of Rheumatology, University of Vienna, Austria

12 Servicio de Medicina Interna, Hospital Vall d’Hebron, Barcelona, Spain

13 Servicio de Reumatologia, Hospital 12 de Octubre, Madrid, Spain

14 Servicio de Medicina Interna, Hospital Clinico Universitario, Granada, Spain

15 Servicio de Reumatologia, Hospital Marques de Valdecillas, Santander, Spain

16 Servizio di Reumatologia ed Immunologia Clinica, Spedali Civili, Brescia, Italy

17 Dept. of Human Genetics, Radboud University Nijmegen Medical Center, The Netherlands

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Journal of Translational Medicine 2010, 8(Suppl 1):P46  doi:10.1186/1479-5876-8-S1-P46

The electronic version of this article is the complete one and can be found online at: http://www.translational-medicine.com/content/8/S1/P46


Published:25 November 2010

© 2010 Broen et al; licensee BioMed Central Ltd.

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 we here investigate the role of the PBEF -1001T>G and PBEF -1543C>T polymorphisms in the genetic predisposition to systemic sclerosis (SSc) susceptibility and pulmonary involvement.

Patients and methods

We genotyped DNA from 2737 SSc patients and 1913 matched healthy controls, both from 8 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 1.05-1.37). In addition, these subjects showed an increased decline in forced vital capacity (FVC) over 15 years follow-up (P=0.02) (HR 1.64, 95%CI: 1.02-2.64) 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: 1.52-7.12).

Conclusions

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