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. 2013;8(1):e54419.
doi: 10.1371/journal.pone.0054419. Epub 2013 Jan 23.

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

F David Carmona  1 , Jose-Ezequiel Martin, Lorenzo Beretta, Carmen P Simeón, Patricia E Carreira, José Luis Callejas, Mónica Fernández-Castro, Luis Sáez-Comet, Emma Beltrán, María Teresa Camps, María Victoria Egurbide; Spanish Scleroderma Group; Paolo Airó, Raffaella Scorza, Claudio Lunardi, Nicolas Hunzelmann, Gabriela Riemekasten, Torsten Witte, Alexander Kreuter, Jörg H W Distler, Rajan Madhok, Paul Shiels, Jacob M van Laar, Carmen Fonseca, Christopher Denton, Ariane Herrick, Jane Worthington, Annemie J Schuerwegh, Madelon C Vonk, Alexandre E Voskuyl, Timothy R D J Radstake, Javier Martín
Collaborators, Affiliations

The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis

F David Carmona et al. PLoS One. 2013.

Abstract

Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P = 1.34×10(-8), OR = 1.22, CI 95% = 1.14-1.30; rs2004640: P = 4.60×10(-7), OR = 0.84, CI 95% = 0.78-0.90; rs10488631: P = 7.53×10(-20), OR = 1.63, CI 95% = 1.47-1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P = 9.04×10(-22), OR = 1.75, CI 95% = 1.56-1.97) better explained the observed association (likelihood P-value = 1.48×10(-4)), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that this association is not sub-phenotype-specific.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

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