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The systemic lupus erythematosus IRF5 risk haplotype is associated with systemic sclerosis.
- Source :
-
PloS one [PLoS One] 2013; Vol. 8 (1), pp. e54419. Date of Electronic Publication: 2013 Jan 23. - Publication Year :
- 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.
- Subjects :
- Alleles
Female
Gene Frequency
Genetic Loci
Humans
Linkage Disequilibrium
Lupus Erythematosus, Systemic complications
Lupus Erythematosus, Systemic ethnology
Male
Phenotype
Risk Factors
Scleroderma, Systemic complications
Scleroderma, Systemic ethnology
White People
Genetic Predisposition to Disease
Haplotypes
Interferon Regulatory Factors genetics
Lupus Erythematosus, Systemic genetics
Polymorphism, Single Nucleotide
Scleroderma, Systemic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23372721
- Full Text :
- https://doi.org/10.1371/journal.pone.0054419