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


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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J Martín and B Rueda contributed equally to this work.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Bossini-Castillo, L., Broen, J., Simeon, C.P. et al. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with Systemic Sclerosis in a large European cohort. J Transl Med 8 (Suppl 1), P5 (2010).

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