Interferon Regulatory Factor 5 Rs2004640 Research Articles

Polymorphisms and haplotypes of IL2RA, IL10, IFNG, IRF5, and CCR2 are associated with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children.

Cytokine storms are central to the development of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Previous studies have shown that single-nucleotide polymorphisms (SNPs) of cytokine genes may be associated with the development of EBV-HLH in children. As such, we investigated the association between susceptibility to EBV-HLH in children and SNPs and haplotypes of genes encoding interleukin-2 receptor subunit alpha (IL2RA), interleukin-10 (IL10), interferon gamma (IFNG), interferon regulatory factor 5 (IRF5), and C-C chemokine receptor 2 (CCR2). Sixty-six children with EBV-HLH and 58 healthy EBV-seropositive controls were enrolled in this study. SNPs of IL2RA rs2104286, rs12722489, and rs11594656; IL10 rs1800896, rs1800871, and rs1800872; IFNG rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were assayed and genotyped using the SNaPshot technique. Frequencies of the A allele of IL2RA rs2104286 and IL10 rs1800896, and C allele of IL-10 rs1800872 were significantly higher in the EBV-HLH group than in the control group. The AA genotype of IL2RA rs2104286 and IL10 rs1800896, and the CC genotype of IL10 rs1800872 might be associated with a significantly high risk of EBV-HLH. However, the frequencies of genotypes and alleles of IL2RA rs2104286, IL10 rs1800871, IFNG rs2430561, IRF5 rs2004640, and CCR2 rs1799864 were similar in both groups. Additionally, IL2RA AGT (rs2104286-rs12722489-rs11594656) and IL10 ACC (rs1800896-rs1800871-rs1800872) haplotypes were also associated with an increased risk of EBV-HLH. SNPs of IL2RA rs2104286, IL10 rs1800896 and rs1800872 and the haplotypes of IL2RA AGT and IL10 ACC were highly associated with susceptibility to EBV-HLH in children.

ROLE OF IRF5 GENE POLYMORPHISM IN PREDISPOSITION TO JUVENILE-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS IN THE BELARUSIAN POPULATION

The IRF5 (interferon regulatory factor 5) gene encoding a transcription factor is involved in the regulation of interferon synthesis and other proinflammatory cytokines. It is assumed that the IRF5 gene is associated with juvenileonset systemic lupus erythematosus (jSLE), a chronic autoimmune disease that develops in childhood and differs from the adult subtype of SLE in a number of its manifestations. The aim of the presented work was to conduct a pilot study of IRF5 rs2004640 polymorphism in the population of children in Belarus and its association with the development of jSLE. Genotyping of DNA samples was performed using real-time PCR in a group of patients diagnosed with
 jSLE (38 people) and in the clinical control group without autoimmune and inflammatory diseases (378 people). The frequency of the IRF5 rs2004640 minor T allele was determined in the Belarusian population of children (under the age of 17). It was found that the rs2004640 TT genotype is associated with the risk of the jSLE development (OR = 2.27; 95% CI 1.08–4.76; p = 0.035) that after further investigations may improve an early diagnosis of jSLE.

Relating Interferon Regulatory Factor 5 Rs2004640 Gene Polymorphism To Increased Risk Of Systemic Sclerosis In The Patients: Russian Federation Cohort

Background ― A number of studies confirmed a crucial role of type 1 interferon in pathophysiology of connective tissue diseases. Interferon regulatory factors (IRF) coordinate an expression of type 1 interferon, while interferon regulatory factor 5 (IRF5) gene was recently identified as causing predisposition to systemic lupus erythematosus and Sjögren syndrome. The objective of our study was to identify possible association of IRF5 rs2004640 (G/T) single nucleotide polymorphism with systemic sclerosis (SSc). Material and Methods―The study involved 236 individuals, including 105 patients with SSc diagnosis and 131 control individuals from Moscow region. The latter were healthy, unrelated to each other, their genders and ages were matched to those of SSc patients. Allele-specific real-time polymerase chain reaction (PCR) was used to study IFR5 rs2004640 polymorphism. Results ― We detected significantly higher percentage of IRF5 T-allele carriers in all patients (59.5%), those with diffuse cutaneous SSc (67.3%), patients with interstitial lung lesions (62.3%), and those with positive titers of anti-topoisomerase I antibodies (66.3%), compared with control group (46.2%). The odds ratios (OR) were: 1.71 (р=0.00), 2.40 (р=0.0004), 1.93 (р=0.002), and 2.30 (р=0.0008), correspondingly. Conclusion ― The replacement of nucleotide G by T in the IRF5 rs2004640 gene polymorphism was associated with a predisposition to SSc. Our data implied an existence of a novel SSc pathogenetic pathway associated with important role of type 1 interferon in pathophysiology of connective tissue diseases.

Association between the interferon regulatory factor 5 rs2004640 functional polymorphism and systemic lupus erythematosus: an updated meta-analysis.

The aim of this study is to determine whether the functional interferon regulatory factor 5 ( IRF5) polymorphism rs2004640 is associated with susceptibility to systemic lupus erythematosus (SLE) in multiple ethnic populations. A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism in all study participants as well as each ethnic population. Twenty research articles that included 28 comparative studies of 20,892 patients and 24,930 controls were included in the meta-analysis. The Asian population had a much lower prevalence of the T allele than any other study population at 28%, and the European population had the highest prevalence of the T allele at 52%. Meta-analysis showed an association between the IRF5 rs2004640 polymorphism and SLE in all participants (odds ratio = 1.472, 95% confidence interval = 1.370-1.582, p < 0.001). Analysis after stratification by ethnicity indicated that the IRF5 rs2004640 T allele is significantly associated with SLE in Europeans, Asians, Latin Americans and Arabs. This meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.

Association of interferon regulatory factor 5 (IRF5) gene polymorphisms with juvenile idiopathic arthritis.

Interferon regulatory factor 5 (IRF5) is a member of IRF family which induce signaling pathways and are involved in modulation of cell growth, differentiation, apoptosis, and immune system activity. Juvenile idiopathic arthritis (JIA) is an auto-inflammatory syndrome where the inflammatory markers are believed to play a fundamental role in its pathogenesis. In this study, we aimed to assess the association of IRF5 gene polymorphisms with susceptibility of JIA in Iranian population. Three IRF5 single-nucleotide polymorphisms (rs10954213 A/G, rs2004640 G/T, and rs3807306 G/T) were genotyped using TaqMan assays in 55 patients with JIA and 63 matched healthy individuals. The frequency of the IRF5 rs2004640 T allele was significantly higher (69 vs 45%, P value = 0.0013) in JIA group as compared to control. The frequency of the IRF5 rs 2004640 G allele was significantly higher in the control group in comparison to JIA group (54 vs 32%, P value = 0.001). Allele and genotype frequencies of the rs10954213 and rs3807306 did not show any significant difference between JIA and control group. IRF5 rs 2004640 T allele can be considered as a risk factor for the development of JIA and presence of rs 2004640 G may be act as protective factor.

The IRF5 rs2004640 (G/T) polymorphism is not a genetic risk factor for systemic lupus erythematosus in population from south India.

Background & objectives:Genetic aberrations disrupting toll-like receptor and interferon homeostasis enhance the risk of systemic lupus erythematosus (SLE). Raised serum interferon-alpha (IFN-α) levels in SLE patients have been ascribed to polymorphism (rs2004640 G/T) in interferon regulatory factor 5 (IRF5) gene, resulting in enhanced transcript splicing. A positive association between IRF5 polymorphism and SLE risk has been reported in many populations. This study was aimed to find out frequency of IRF5 rs2004640 G/T polymorphism in patients with SLE and healthy controls and to assess its influence on susceptibility, clinical and serological characteristics of SLE.Methods:IRF5 rs2004640 (G/T) polymorphism was analyzed in 300 SLE patients and 460 age and sex matched controls by real-time PCR.Results:The IRF5 rs2004640 (G/T) polymorphism did not confer risk of SLE or influence clinical or serological phenotype. However, the mutant allele conferred a borderline risk to develop thrombocytopenia (odds ratio: 2.05, 95% confidence interval: 0.97–4.3, P=0.06) in patients with SLE.Interpretation & conclusions:Our study revealed that the IRF5 rs2004640 polymorphism was not a risk factor for SLE in population from south India. It may, however, be a useful genetic marker for thrombocytopenia in SLE patients. Although we could not demonstrate susceptibility toward lupus in the presence of IRF5 rs2004640 (G/T) polymorphism, further exploration of the genetic variability of IRF5 may help uncover its pathogenic role in Indian SLE patients.

Interferon regulatory factor 5 genetic variants are associated with cardiovascular disease in patients with rheumatoid arthritis.

IntroductionRheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased cardiovascular (CV) disease risk. Interferon regulatory factor 5 (IRF5) is a regulator of type I interferon induction. Recently, researchers have described an association between multiple single-nucleotide polymorphisms of the IRF5 gene and some rheumatic disorders. In this study, we aimed to evaluate whether three different haplotype blocks within the IRF5 locus which have been shown to alter the protein function are involved in the risk of CV events occurring in Spanish RA patients.MethodsThree IRF5 polymorphisms (rs2004640, rs2070197 and rs10954213) representative of each haplotype group were genotyped by performing TaqMan assays using a 7900HT Fast Real-Time PCR System with tissue from a total of 2,137 Spanish patients diagnosed with RA. Among them, 390 (18.2%) had experienced CV events. The relationship of IRF5 genotypes and haplotypes to CV events was tested using Cox regression.ResultsMale sex, age at RA diagnosis and most traditional risk factors (hypertension, dyslipidemia and smoking habit) were associated with increased risk for CV events in the RA population. Interestingly, a protective effect of both IRF5 rs2004640 GG and IRF5 rs10954213 GG genotypes against the risk for CV events after adjusting the results for sex, age at RA diagnosis and traditional CV disease risk factors was observed (hazard ratio (HR) = 0.6, 95% confidence interval (CI) = 0.38 to 0.92, P = 0.02; and HR = 0.58, 95% CI = 0.36 to 0.95, P = 0.03, respectively). Moreover, we detected a protective effect of the GTG haplotype against the risk for CV events after adjusting the results for potential confounding factors (HR = 0.72, 95% CI = 0.56 to 0.93, P = 0.012).ConclusionsOur results reveal that IRF5 gene variants are associated with risk of CV events in patients with RA.

Association of the IRF5 rs2004640 polymorphism with rheumatoid arthritis: a meta-analysis

Several molecular epidemiological studies have been conducted in recent years to evaluate a possible association between the interferon regulatory factor 5 (IRF5) rs2004640 polymorphism and rheumatoid arthritis risk in diverse populations. However, the results remain conflicting rather than conclusive. Our aim was to assess associations of IRF5 gene polymorphisms with rheumatoid arthritis risk. Meta-analysis was performed on six published case-control studies (from eight countries) that included 4,818 cases of rheumatoid arthritis and 4,316 controls. The rs2004640-T allele was associated with a significantly increased risk of rheumatoid arthritis when the dominant genetic model was applied (T/T + T/G versus G/G: P = 0.003, OR = 1.14, 95% CI 1.05-1.25). Upon stratified analysis by ethnicity, the rs2004640 polymorphism was associated with an increased rheumatoid arthritis risk in Caucasians when the homozygotic contrast model was employed(T/T versus G/G: P = 0.03, OR = 1.25, 95% CI 1.02-1.53) and this was also the case when the dominant genetic model was used (T/T + T/G versus G/G: P = 0.04, OR = 1.20, 95% CI 1.01-1.42), whereas, in Asian populations, only the dominant genetic model was associated with an increased rheumatoid arthritis risk (T/T + T/G versus G/G: P = 0.02, OR = 1.14, 95% CI 1.02-1.26). The results suggest that the IRF5 rs2004640 polymorphism is associated with rheumatoid arthritis especially when the dominant genetic model is applied.

Associations between interferon regulatory factor 5 polymorphisms and rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether interferon regulatory factor 5 (IRF5) polymorphisms confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. We searched the literature using the Pubmed and Embase databases and conducted meta-analyses on associations between the four IRF5 polymorphisms (rs2004640, rs729302, rs752637, and rs2280714) and RA susceptibility, using fixed and random effects models. A total of 12 comparison studies were considered in this meta-analysis, which in total involved 7,916 RA patients and 6,452 controls, and eight European, three Asian, and one Argentinean population. Meta-analysis showed an association between the minor allele of rs2004640 and RA in all subjects (odds ratio [OR]=0.928, 95% confidence interval [CI]=0.865-0.996, P=0.037). After stratification by ethnicity, analysis indicated that the minor allele was significantly associated with RA in Europeans (OR=0.889, 95% CI=0.839-0.941, P=5.03×10(-6)), but not in Asians (OR=1.057, 95% CI=0.978-1.144, P=0.164). A direct comparison between anti-citrullinated peptide antibody-positive and -negative patients revealed no difference of the frequency of the rs2004640 minor allele (OR=1.047, 95% CI=0.813-1.348, P=0.724). Meta-analysis identified a significant association between RA and the minor allele of the rs729302 polymorphism in the overall population (OR=0.896, 95% CI=0.826-0.972, P=0.009) and in Asians (OR=0.862, 95% CI=0.795-0.935, P=3.50×10(-5)), but not in Europeans (OR=0.951, 95% CI=0.877-1.031, P=0.225). Meta-analysis showed an association between the minor allele of rs752637 and RA in Europeans (OR=0.858, 95% CI=0.789-0.932, P=3.03×10(-5)), but not in Asians (OR=1.035, 95% CI=0.918-1.168, P=0.572). No association was found between the rs2280714 polymorphism and RA susceptibility. This meta-analysis confirms that the IRF5 rs2004640, rs729302 and rs752637 polymorphisms are associated with RA susceptibility in different ethnic groups, especially in Europeans and Asians, but further study of this association is required in other ethnic groups.

A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus

To more precisely estimate the association between interferon regulatory factor 5 (IRF5) polymorphisms and systemic lupus erythematosus (SLE) risk, we surveyed studies on the association of IRF5 rs2204640, rs10954213, rs729302 or rs2280714 with SLE using PubMed, Embase and Web of Science up to February 2011. Two investigators independently assessed the data quality and extracted the data. A total of 17 comparisons from ten relevant studies involving 6403 patients and 7475 controls were included to analyse the association between IRF5 rs2004640 and SLE risk (odds ratio, OR = 1.41, 95% confidence interval (CI) 1.34-1.49, P = 0.000). As for rs10954213, there were ten comparisons from six relevant studies involving 3461 patients and 3692 controls were included to analyse the association between IRF5 rs10954213 and SLE risk (OR = 1.23, 95% CI 1.08-1.39, P = 0.002). And this meta-analysis also showed a significant association of rs729302 (OR = 0.78, 95% CI 0.74-0.83, P = 0.000), rs2280714 (OR = 0.90, 95% CI 0.83-0.98, P = 0.021) with SLE. In a subgroup analysis by ethnicity, significantly increased SLE risk was associated with IRF5 rs2004640 T allele in populations of European, Asian and Latin American origin, and the rs10954213 A allele is significantly associated with SLE in European origin but not in Asian origin. This meta-analysis suggested that IRF5 gene polymorphism was associated with SLE in multiple ethnic populations.

Association of IRF5 gene polymorphisms and lupus nephritis in a Chinese population

Recently, several studies have provided convincing evidence that polymorphisms in the interferon regulatory factor 5 (IRF5) gene were significantly associated with systemic lupus erythematosus (SLE) in several populations. The aim of this study was to investigate the association between IRF5 and lupus nephritis in a Chinese cohort and analyze the relationship between the rs2004640 genotype and the clinical and pathological phenotypes of lupus nephritis. The IRF5 rs2004640 polymorphism in a cohort of 190 Chinese lupus nephritis patients and 182 healthy Chinese blood donors was analyzed. The polymorphism examined was genotyped using the TaqMan assay. RESULTS The IRF5 rs2004640 T allele was associated with the susceptibility to lupus nephritis (rs2004640 T, 41.6% in patients, 30.8% in healthy controls, odds ratio=1.6, P=0.002). It was also found that the Chinese population had a much lower minor allele frequency of rs2004640 than Western populations studied to date. In the present cohort, 30.8% individuals in the control group had the detrimental T allele, compared to frequencies in the range of 44-56% that exist in Western populations. No association was found between IRF5 rs2004640 and pathology, or clinical presentation of lupus nephritis in the Chinese cohort examined. The results suggested that the rs2004640 T allele was associated with susceptibility to lupus nephritis and that the IRF5 polymorphism analyzed did not seem to be implicated in the pathology and clinical manifestation of lupus nephritis in the Chinese population.

Association of Polymorphisms in Interferon Regulatory Factor 5 Gene with Rheumatoid Arthritis: A Metaanalysis

We investigated potential associations between rheumatoid arthritis (RA) and interferon regulatory factor 5 (IRF5) polymorphisms in a metaanalysis. This metaanalysis included 5 case-control studies, which provided a total of 6582 RA cases and 5375 controls. Odds ratios (OR) were employed to evaluate the risk of RA according to the 4 single-nucleotide polymorphisms (SNP) in IRF5 (rs729302, rs2004640, rs752637, and rs2280714) and data were analyzed in respect to association between alleles. Among 4 candidate SNP, rs729302, rs2004640, and rs2280714 were statistically significant; both allele C of rs729302 and allele G of rs2004640 within the promoter region of IRF5 were associated with a protective effect [random-effects (RE) OR 0.889, 95% confidence interval (CI) 0.803-0.977, p=0.015 for rs729302; and RE OR 0.905, 95% CI 0.848-0.965, p=0.002 for rs2004640]. Similar results were also obtained in T allele of rs2280714 in the 3'-untranslated region (RE OR 0.927, 95% CI 0.866-0.992, p=0.029). There was no evidence of publication bias from funnel-plot asymmetry and Egger's regression test. Our metaanalysis supported the evidence of the significant role of IRF5 polymorphisms in RA.

Association between the rs2004640 functional polymorphism of interferon regulatory factor 5 and systemic lupus erythematosus: a meta-analysis

The aim of this study is to determine whether the functional interferon regulatory factor 5 (IRF5) polymorphism, rs2004640, confers susceptibility to systemic lupus erythematosus (SLE) in multiple ethic populations. A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism and 12 studies were included in the meta-analysis. Meta-analysis revealed an association between SLE and the IRF5 rs2004640 T allele in all subjects without inter-study heterogeneity (OR 1.429, 95% CI 1.359-1.503, P < 0.001). The IRF5 rs2004640 T allele was significantly associated with SLE in European and Asians. The Asian population had a much lower prevalence of the T allele (34.4%) than any other population studied. and Europeans had the highest frequency of the IRF5 rs2004640 T allele (51.8%). In conclusion, this meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.

Putative Role of Functional Interferon Regulatory Factor 5 (IRF5) Polymorphism in Rheumatoid Arthritis in a Korean Population

.Recent studies suggest that polymorphisms of interferon regulatory factor 5 (IRF5) are significantly associated with systemic lupus erythematosus in several populations. The effect of IRF5 polymorphism on susceptibility to rheumatoid arthritis (RA) has been investigated, and the results were inconsistent. We analyzed the genetic effects of IRF5 polymorphisms on RA in a Korean population. Eight single-nucleotide polymorphisms (SNP) and 2 insertion-deletion polymorphisms in IRF5 were genotyped in 2183 subjects (1204 RA cases and 979 controls) using the TaqMan(R) method. The genetic effects of SNP on the risk of RA were evaluated using chi-square tests and multivariate logistic regression, controlling for age, sex, and shared epitope (SE), and we then performed conditional analysis by SE status and anti-cyclic citrullinated peptide (anti-CCP) antibody (Ab) status. Data from a Mantel-Haenszel metaanalysis of odds ratios (OR) were subsequently combined in a separate analysis with the results of the association of rs2004640 with RA from a previous study. Two of the IRF5 polymorphisms, CGGGGindel (OR 1.38, 95% CI 1.09-1.76, pcorr = 0.04) and rs2004640 (OR 1.36, 95% CI 1.09-1.68, pcorr = 0.03), and one haplotype, including the rs2004640 and the CGGGGindel, ht3 (A-Del-T-C-del-A-T) (OR 1.39, 95% CI 1.09-1.79, pcorr = 0.04) were significantly associated with an increased risk of RA. After stratification according to anti-CCP Ab and SE status, rs2004640 SNP was associated with the anti-CCP Ab-positive (OR 1.47, 95% CI 1.15-1.88, pcorr = 0.01) or SE-positive group (OR 1.54, 95% CI 1.14-2.09, pcorr = 0.03). A combined analysis including all 3 independent cohorts from the previous study revealed an association of the rs2004640 with RA (pooled OR 1.21, 95% CI 1.07-1.38, pooled p = 0.0031 in dominant model). Our results suggest that the IRF5 polymorphism is associated with genetic susceptibility to RA at least in a Korean population, and that it may contribute to disease susceptibility in SE-positive or anti-CCP Ab-positive patients with RA.

Association of IRF5 gene polymorphisms with rheumatoid arthritis in a Tunisian population

Objective: A strong genetic association of rheumatoid arthritis (RA) with the interferon regulatory factor 5 (IRF5) gene has been described previously in a Swedish population, although this result was not confirmed in a French population. We undertook an association study between IRF5 and the RA phenotype, as well as a study with serological markers of RA, in a Tunisian population.Methods: A single‐nucleotide polymorphism (SNP; rs2004640) was genotyped using a Taqman 5′ allelic discrimination assay on an ABI 7500 real‐time polymerase chain reaction (PCR) instrument in 140 RA patients and 185 controls. Rheumatoid factor (RF) and anti‐citrullinated protein/peptide antibodies (ACPA) were determined by enzyme‐linked immunosorbent assay (ELISA). Association was assessed based on the χ2 test and odds ratios (ORs) with 95% confidence intervals (CIs).Results: The frequency of the TT genotype of the IRF5 SNP rs2004640 differed significantly between patients and controls (p = 0.01). This difference was greater when a subgroup of patients with another ‘autoimmune’ disorder was considered (p = 0.007). A weak but significant association was also found in a subgroup of patients who were positive for ACPA (p = 0.04) or erosion (p = 0.01).Conclusions: Our results indicate that the TT genotype of the IRF5 (rs2004640) dimorphism is associated with RA in a Tunisian population.