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

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A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with Systemic Sclerosis in a large European cohort

L Bossini-Castillo1, JCA Broen2, C P Simeon3, L Beretta4, M C Vonk2, N Ortego-Centeno5, G Espinosa6, P Carreira7, M T Camps8, N Navarrete9, M F González-Escribano10, E Vicente-Rabaneda11, L Rodríguez12, C Tolosa13, J A Román-Ivorra14, I Gómez-Gracia15, F J García-Hernández16, I Castellví17, M Gallego18, A Fernández-Nebro19, M V Egurbide20, V Follonosa3, P García de la Peña21, A Pros22, M A González-Gay23, R Hesselstrand24, G Riemekasten25, T Witte26, MJH Coenen27, B P Koeleman28, F Houssiau29, V Smith30, F De Keyser30, R Westhovens31, E De Langhe31, A E Voskuyl32, A J Schuerwegh33, M M Chee34, R Madhok34, P Shiels34, C Fonseca35, C Denton35, K Claes36, L Padykov37, A Nordin37, Ø Palm38, B A Lie39, P Airó40, R Scorza4, J M van Laar41, N Hunzelmann42, A Kreuter43, A Herrick44, J Worthington44, TRDJ Radstake2, J Martín1 and B Rueda110*

  • * Corresponding author: B Rueda

  • † Equal contributors

Author Affiliations

1 Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain

2 Dept. of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

3 Servicio de Medicina Interna, Hospital Valle de Hebron, Barcelona, Spain

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

5 Servicio de Medicina Interna, Hospital Clínico Universitario, Granada, Spain

6 Servicio de Medicina Interna, Hospital Clínico de Barcelona, Barcelona, Spain

7 Servicio de Reumatología, Hospital 12 de Octubre, Madrid, Spain

8 Servicio de Medicina Interna, Hospital Carlos-Haya, Málaga, Spain

9 Servicio de Medicina Interna, Hospital Virgen de las Nieves, Granada, Spain

10 Servicio de Inmunología, Hospital Virgen del Rocío, Sevilla, Spain

11 Servicio de Reumatología, Hospital de la Princesa, Madrid, Spain

12 Servicio de Reumatología, Hospital Clinico San Carlos, Madrid, Spain

13 Servicio de Medicina Interna, Hospital Parc Tauli,Sabadell, Spain

14 Servicio de Reumatología, Hospital del Doctor Peset Aleixandre, Valencia, Spain

15 Servicio de Reumatología, Hospital Reina Sofía, Córdoba, Spain

16 Servicio de Medicina Interna, Hospital Virgen del Rocío, Sevilla, Spain

17 Servicio de Reumatología, Hospital de Sant Pau, Barcelona, Spain

18 Servicio de Medicina Interna, Hospital Central de Asturias, Oviedo, Spain

19 Servicio de Reumatología, Hospital Carlos Haya, Málaga, Spain

20 Servicio de Medicina Interna, Hospital de Cruces, Barakaldo, Spain

21 Servicio de Reumatología, Hospital Ramón y Cajal, Madrid, Spain

22 Servicio de Reumatología, Hospital Del Mar, Barcelona, Spain

23 Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, Santander, Spain

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

25 Dept. of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany

26 Hannover Medical School, Hannover, Germany

27 Dept. of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

28 Section Complex Genetics, Dept. of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

29 Université catholique de Louvain (UCL), Brussels, Belgium

30 University of Ghent, Ghent, Belgium

31 University of Leuven (KULeuven), Leuven, Belgium

32 Dept. of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands

33 Dept. of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

34 University of Glasgow, Glasgow, UK

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

36 Dept. of Genetics, University of Ghent, Ghent, Belgium

37 Karolinska Institute, Stockholm, Sweden

38 Dept. of Rheumatology, Rikshospitalet, Oslo University Hospital, Oslo, Norway

39 Institute of Immunology, Rikshospitalet, Oslo University Hospital, Oslo, Norway

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

41 Institute of Cellular Medicine, Newcastle University, Newcastle, UK

42 Dept. of Dermatology, University of Cologne, Cologne, Germany

43 Ruhr University of Bochum, Bochum, Germany

44 Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

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Journal of Translational Medicine 2010, 8(Suppl 1):P5  doi:10.1186/1479-5876-8-S1-P5

The electronic version of this article is the complete one and can be found online at:

Published:25 November 2010

© 2010 Rueda et al; licensee BioMed Central Ltd.


The TNFSF4 gene, which encodes OX40L, is considered as a potential autoimmunity candidate gene. OX40L is expressed on activated antigen presenting cells (APCs) and endothelial cells in acute inflammation [1]. Furthermore, it enhances B-cell proliferation and differentiation, and its binding to OX40 (CD134) promotes proliferation and survival of T-cells and predisposes them to a more permissive proliferative and survival condition [2]. Interestingly, four TNFSF4 promoter single-nucleotide polymorphisms (SNP) were recently implicated in susceptibility to systemic sclerosis (SSc)[3].


The aim of this study was to confirm the influence of TNFSF4 polymorphisms on SSc susceptibility and clinical subtypes or phenotypic features.

Patients and methods

Eight European populations of Caucasian ancestry were included, comprising a total of 3014 SSc patients and 3125 healthy controls. Four genetic variants of the TNFSF4 gene (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers and genotyped using Taqman Allelic Discrimination Assays.


A pooled-analysis revealed the association of rs1234314 and rs12039904 SNPs with SSc [OR=1.15,95%CI 1.02-1.31;OR=1.18,95%CI 1.08-1.29, respectively].

After subtype stratification, significant association of the four tested SNPs with the limited cutaneous SSc (lcSSc) subgroup of patients was revealed [rs1234314 OR=1.22,95%CI 1.07-1.38; rs844644 OR=0.91,95%CI 0.83-0.99; rs844648 OR=1.10,95%CI 1.01-1.20; and rs12039904 OR=1.20,95%CI 1.09-1.33]. Considering autoantibody status, the association of three of these variants, rs1234314, rs844648 and rs12039904 with anticentromere autoantibody (ACA) positive subset of patients remained significant [OR=1.23,95%CI 1.10-1.37; OR=1.12,95%CI 1.01-1.25; OR=1.22,95%CI 1.07-1.38, respectively]. Haplotype analysis confirmed the existence of a previously described protective haplotype and revealed a new risk haplotype with evidence of association with SSc [OR=0.88,95%CI 0.82-0.96;OR=1.14,95%CI 1.03-1.26, respectively], lcSSc [OR=0.88,95%CI 0.80-0.96; OR=1.20,95%CI 1.08-1.35, respectively] and ACA positive subgroups[OR=0.86,95%CI 0.77-0.97;OR=1.23, 95%CI 1.07-1.42, respectively].


Our data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially with lcSSc and ACA positive subsets of patients.


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