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

DOI: 10.1186/1479-5876-8-S1-P5

Published: 25 November 2010

Introduction

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].

Aim

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.

Results

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].

Conclusions

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

Notes

Authors’ Affiliations

(1)
Instituto de Parasitología y Biomedicina López-Neyra, CSIC
(2)
Dept. of Rheumatology, Radboud University Nijmegen Medical Centre
(3)
Servicio de Medicina Interna, Hospital Valle de Hebron
(4)
Referral Center for Systemic Autoimmune Diseases, University of Milan
(5)
Servicio de Medicina Interna, Hospital Clínico Universitario
(6)
Servicio de Medicina Interna, Hospital Clínico de Barcelona
(7)
Servicio de Reumatología, Hospital 12 de Octubre
(8)
Servicio de Medicina Interna, Hospital Carlos-Haya
(9)
Servicio de Medicina Interna, Hospital Virgen de las Nieves
(10)
Servicio de Inmunología, Hospital Virgen del Rocío
(11)
Servicio de Reumatología, Hospital de la Princesa
(12)
Servicio de Reumatología, Hospital Clinico San Carlos
(13)
Servicio de Medicina Interna, Hospital Parc Tauli
(14)
Servicio de Reumatología, Hospital del Doctor Peset Aleixandre
(15)
Servicio de Reumatología, Hospital Reina Sofía
(16)
Servicio de Medicina Interna, Hospital Virgen del Rocío
(17)
Servicio de Reumatología, Hospital de Sant Pau
(18)
Servicio de Medicina Interna, Hospital Central de Asturias
(19)
Servicio de Reumatología, Hospital Carlos Haya
(20)
Servicio de Medicina Interna, Hospital de Cruces
(21)
Servicio de Reumatología, Hospital Ramón y Cajal
(22)
Servicio de Reumatología, Hospital Del Mar
(23)
Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla
(24)
Dept. of Rheumatology, Lund University Hospital
(25)
Dept. of Rheumatology and Clinical Immunology, Charité University Hospital
(26)
Hannover Medical School
(27)
Dept. of Human Genetics, Radboud University Nijmegen Medical Centre
(28)
Section Complex Genetics, Dept. of Medical Genetics, University Medical Center Utrecht
(29)
Université catholique de Louvain (UCL)
(30)
University of Ghent
(31)
University of Leuven (KULeuven)
(32)
Dept. of Rheumatology, VU University Medical Center
(33)
Dept. of Rheumatology, Leiden University Medical Center
(34)
University of Glasgow
(35)
Centre for Rheumatology, Royal Free and University College Medical School
(36)
Dept. of Genetics, University of Ghent
(37)
Karolinska Institute
(38)
Dept. of Rheumatology, Rikshospitalet, Oslo University Hospital
(39)
Institute of Immunology, Rikshospitalet, Oslo University Hospital
(40)
Servizio di Reumatologia ed Immunologia Clinica Spedali Civili
(41)
Institute of Cellular Medicine, Newcastle University
(42)
Dept. of Dermatology, University of Cologne
(43)
Ruhr University of Bochum
(44)
Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester Academic Health Science Centre

References

  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

Copyright

© Rueda et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.

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