TY - JOUR
T1 - The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis
AU - Carmona, F. David
AU - Martin, Jose Ezequiel
AU - Beretta, Lorenzo
AU - Simeón, Carmen P.
AU - Carreira, Patricia E.
AU - Callejas, José Luis
AU - Fernández-Castro, Mónica
AU - Sáez-Comet, Luis
AU - Beltrán, Emma
AU - Camps, María Teresa
AU - Egurbide, María Victoria
AU - Airó, Paolo
AU - Scorza, Raffaella
AU - Lunardi, Claudio
AU - Hunzelmann, Nicolas
AU - Riemekasten, Gabriela
AU - Witte, Torsten
AU - Kreuter, Alexander
AU - Distler, Jörg H.W.
AU - Madhok, Rajan
AU - Shiels, Paul
AU - van Laar, Jacob M.
AU - Fonseca, Carmen
AU - Denton, Christopher
AU - Herrick, Ariane
AU - Worthington, Jane
AU - Schuerwegh, Annemie J.
AU - Vonk, Madelon C.
AU - Voskuyl, Alexandre E.
AU - Radstake, Timothy R.D.J.
AU - Martín, Javier
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/1/29
Y1 - 2013/1/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84872779755&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0054419
DO - 10.1371/journal.pone.0054419
M3 - Journal articles
C2 - 23372721
AN - SCOPUS:84872779755
VL - 8
JO - PLoS ONE
JF - PLoS ONE
IS - 1
M1 - e54419
ER -