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IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis.

ABSTRACT: BACKGROUND: Recently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640-T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene. AIM: To test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA. PATIENTS AND METHODS: 100 French Caucasian trio families with RA were genotyped and analysed with the transmission disequilibrium test, the frequency comparison of the transmitted and untransmitted alleles, and the genotype relative risk. 97% power was available to detect at least a trend in favour of a factor similar to that reported for SLE. RESULTS: The analysis showed the absence of linkage and association globally and in "autoimmune" RA subsets, with a weak non-significant trend against the IRF5 rs20046470-T allele. Given the robustness of familial-based analysis, this slight negative trend provided strong evidence against even a weaker factor than that reported for SLE. CONCLUSION: Our results exclude the IRF5 rs2004640-T allele as a major genetic factor for RA in this French Caucasian population.

SUBMITTER: Garnier S

PROVIDER: S-EPMC1954661 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis.

Garnier Sophie S Dieudé Philippe P Michou Laetitia L Barbet Sandra S Tan Alice A Lasbleiz Sandra S Bardin Thomas T Prum Bernard B Cornélis François F

Annals of the rheumatic diseases 20061207 6

<h4>Background</h4>Recently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640-T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene.<h4>Aim</h4>To test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA.<h4>Patients and ...[more]

PMID: 17158136

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Project description:BackgroundClinical and epidemiological studies have suggested systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are comorbidities and common genetic etiologies can partly explain such coexistence. However, shared genetic determinations underlying the two diseases remain largely unknown.MethodsOur analysis relied on summary statistics available from genome-wide association studies of SLE (N = 23,210) and RA (N = 58,284). We first evaluated the genetic correlation between RA and SLE through the linkage disequilibrium score regression (LDSC). Then, we performed a multiple-tissue eQTL (expression quantitative trait loci) weighted integrative analysis for each of the two diseases and aggregated association evidence across these tissues via the recently proposed harmonic mean P-value (HMP) combination strategy, which can produce a single well-calibrated P-value for correlated test statistics. Afterwards, we conducted the pleiotropy-informed association using conjunction conditional FDR (ccFDR) to identify potential pleiotropic genes associated with both RA and SLE.ResultsWe found there existed a significant positive genetic correlation (r g = 0.404, P = 6.01E-10) via LDSC between RA and SLE. Based on the multiple-tissue eQTL weighted integrative analysis and the HMP combination across various tissues, we discovered 14 potential pleiotropic genes by ccFDR, among which four were likely newly novel genes (i.e., INPP5B, OR5K2, RP11-2C24.5, and CTD-3105H18.4). The SNP effect sizes of these pleiotropic genes were typically positively dependent, with an average correlation of 0.579. Functionally, these genes were implicated in multiple auto-immune relevant pathways such as inositol phosphate metabolic process, membrane and glucagon signaling pathway.ConclusionThis study reveals common genetic components between RA and SLE and provides candidate associated loci for understanding of molecular mechanism underlying the comorbidity of the two diseases.

Project description:BackgroundRheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.MethodsWe tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus.ResultsA SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81x10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87x10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis.ConclusionsA haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.

Project description: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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IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis.

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IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not associated with rheumatoid arthritis.

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