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The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis

Lookup NU author(s): Professor Jaap Van Laar



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 = 1.34x10(-8), OR = 1.22, CI 95% = 1.14-1.30; rs2004640: P = 4.60x10(-7), OR = 0.84, CI 95% = 0.78-0.90; rs10488631: P = 7.53x10(-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 = 9.04x10(-22), OR = 1.75, CI 95% = 1.56-1.97) better explained the observed association (likelihood P-value = 1.48x10(-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.

Publication metadata

Author(s): Carmona FD, Martin JE, Beretta L, Simeon CP, Carreira PE, Callejas JL, Fernandez-Castro M, Saez-Comet L, Beltran E, Camps MT, Egurbide MV, Airo P, Scorza R, Lunardi C, Hunzelmann N, Riemekasten G, Witte T, Kreuter A, Distler JHW, Madhok R, Shiels P, van Laar JM, Fonseca C, Denton C, Herrick A, Worthington J, Schuerwegh AJ, Vonk MC, Voskuyl AE, Radstake TRDJ, Martin J, Spanish Scleroderma Grp

Publication type: Article

Publication status: Published

Journal: PLoS One

Year: 2013

Volume: 8

Issue: 1

Print publication date: 23/01/2013

Date deposited: 03/07/2013

ISSN (electronic): 1932-6203

Publisher: Public Library of Science


DOI: 10.1371/journal.pone.0054419


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Funder referenceFunder name
Dutch Arthritis Foundation (National Reumafonds)
Instituto de Salud Carlos III (ISCIII), Spain within the VI PN de I+D+i (FEDER)
RETICS Program
VIDI laureate from the Dutch Association of Research (NWO)
Consejo Superior de Investigaciones Cientificas (CSIC) through the program JAE-DOC
European League Against Rheumatism (EULAR)
GEN-FER from the Spanish Society of Rheumatology
CTS-180Junta de Andalucia
CTS-4977Junta de Andalucia
SAF2009-11110Spanish Ministry of Science
PI-0590-2010Consejeria de Salud y Bienestar Social, Junta de Andalucia, Spain
PI-0590-2010Consejeria de Salud, Junta de Andalucia
WI 1031/6.1DFG