The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis.
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.
Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain. dcarmona@ipb.csic.es
F David
FD
Carmona
Jose-Ezequiel
JE
Martin
Lorenzo
L
Beretta
Carmen P
CP
Simeón
Patricia E
PE
Carreira
José Luis
JL
Callejas
Mónica
M
Fernández-Castro
Luis
L
Sáez-Comet
Emma
E
Beltrán
María Teresa
MT
Camps
María Victoria
MV
Egurbide
Paolo
P
Airó
Raffaella
R
Scorza
Claudio
C
Lunardi
Nicolas
N
Hunzelmann
Gabriela
G
Riemekasten
Torsten
T
Witte
Alexander
A
Kreuter
Jörg H W
JH
Distler
Rajan
R
Madhok
Paul
P
Shiels
Jacob M
JM
van Laar
Carmen
C
Fonseca
Christopher
C
Denton
Ariane
A
Herrick
Jane
J
Worthington
Annemie J
AJ
Schuerwegh
Madelon C
MC
Vonk
Alexandre E
AE
Voskuyl
Timothy R D J
TR
Radstake
Javier
J
Martín
D000483:Alleles; D005260:Female; D005787:Gene Frequency; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012595:Scleroderma, Systemic / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D044465:White People
C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors