Volume 8 Supplement 1

5th European Workshop on Immune-Mediated Inflammatory Diseases

Open Access

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 Rueda1, 10
Contributed equally
Journal of Translational Medicine20108(Suppl 1):P5


Published: 25 November 2010


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.


Authors’ Affiliations

Instituto de Parasitología y Biomedicina López-Neyra, CSIC
Dept. of Rheumatology, Radboud University Nijmegen Medical Centre
Servicio de Medicina Interna, Hospital Valle de Hebron
Referral Center for Systemic Autoimmune Diseases, University of Milan
Servicio de Medicina Interna, Hospital Clínico Universitario
Servicio de Medicina Interna, Hospital Clínico de Barcelona
Servicio de Reumatología, Hospital 12 de Octubre
Servicio de Medicina Interna, Hospital Carlos-Haya
Servicio de Medicina Interna, Hospital Virgen de las Nieves
Servicio de Inmunología, Hospital Virgen del Rocío
Servicio de Reumatología, Hospital de la Princesa
Servicio de Reumatología, Hospital Clinico San Carlos
Servicio de Medicina Interna, Hospital Parc Tauli
Servicio de Reumatología, Hospital del Doctor Peset Aleixandre
Servicio de Reumatología, Hospital Reina Sofía
Servicio de Medicina Interna, Hospital Virgen del Rocío
Servicio de Reumatología, Hospital de Sant Pau
Servicio de Medicina Interna, Hospital Central de Asturias
Servicio de Reumatología, Hospital Carlos Haya
Servicio de Medicina Interna, Hospital de Cruces
Servicio de Reumatología, Hospital Ramón y Cajal
Servicio de Reumatología, Hospital Del Mar
Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla
Dept. of Rheumatology, Lund University Hospital
Dept. of Rheumatology and Clinical Immunology, Charité University Hospital
Hannover Medical School
Dept. of Human Genetics, Radboud University Nijmegen Medical Centre
Section Complex Genetics, Dept. of Medical Genetics, University Medical Center Utrecht
Université catholique de Louvain (UCL)
University of Ghent
University of Leuven (KULeuven)
Dept. of Rheumatology, VU University Medical Center
Dept. of Rheumatology, Leiden University Medical Center
University of Glasgow
Centre for Rheumatology, Royal Free and University College Medical School
Dept. of Genetics, University of Ghent
Karolinska Institute
Dept. of Rheumatology, Rikshospitalet, Oslo University Hospital
Institute of Immunology, Rikshospitalet, Oslo University Hospital
Servizio di Reumatologia ed Immunologia Clinica Spedali Civili
Institute of Cellular Medicine, Newcastle University
Dept. of Dermatology, University of Cologne
Ruhr University of Bochum
Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre


  1. Manku H, Graham DS, Vyse TJ: Association of the co-stimulator OX40L with systemic lupus erythematosus. J Mol Med. 2009, 87: 229-234.View ArticlePubMedGoogle Scholar
  2. Gough MJ, Weinberg AD: OX40 (CD134) and OX40L. Adv Exp Med Biol. 2009, 647: 94-107.View ArticlePubMedGoogle Scholar
  3. Gourh P, Arnett FC, Tan FK, Assassi S, Divecha D, Paz G: Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. Ann Rheum Dis. 2010, 69: 550-555.PubMed CentralView ArticlePubMedGoogle Scholar


© Rueda et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.