IL-1ra Polymorphisms Research Articles

Impact of interleukin-1 gene polymorphisms on the severity of COVID-19

The severity of Coronavirus Disease 2019 (COVID-19) has been closely linked to an exacerbated proinflammatory response and cytokine storm. Interleukin-1 (IL-1), a pivotal proinflammatory cytokine, plays a crucial role in the development of acute respiratory distress syndrome (ARDS) and multiorgan dysfunction. Single nucleotide polymorphisms within the IL-1 gene have been shown to modulate IL-1 cytokine levels. This study aimed to investigate the association of IL-1 gene polymorphisms (IL-1 + 3953C > T, IL-1β -511 T > C, and IL-1Ra) with the severity of COVID-19. Genotyping of IL-1 gene polymorphisms (IL-1 + 3953C > T, IL-1β -511 T > C) were performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), while IL-1Ra genotyping was done by Random Amplification of Polymorphic DNA (RAPD). PCR-RFLP data were validated through Sanger sequencing (SeqStudio Genetic Analyzer). Data analysis was carried out by SPSS-v21 and SHesis (online version). The frequency of the T allele of the IL-1 + 3953C > T polymorphism was found to be higher in mild cases as compared to severe cases, demonstrating a significant protective effect against COVID-19 severity (P = 0.001). However, no significant associations were observed for IL-1β -511 T > C and IL-1Ra polymorphisms (P > 0.05). In haplotype analysis (between IL-1 + 3953C > T, and IL-1β -511 T > C gene polymorphisms), individual with CT haplotype showed a higher risk of severity (OR = 1.8, P = 0.001), while individuals with TT haplotype showed significant protection against severity (P = 0.001). Our findings suggest that the T allele of IL-1β + 3953C > T polymorphism may confer protective effect against the severity of COVID-19.

Association between interleukin-1 receptor polymorphism and human herpesvirus 8 among lymphoma patients

Abstract Background: Human herpesvirus 8 (HHV-8) stimulates lymphoproliferation, by activating the signaling pathway of the interleukin-6 receptor, along with several other regulatory mechanisms. The presence of specific genetic variations governing immune responses can impact the promotion or suppression of malignant lymphoma. Polymorphisms in the gene cluster of interleukin-1 (IL-1) have been identified as significant contributors to the regulation of inflammation. Objective: This study aimed to determine the percentage HHV-8 and whether polymorphisms at IL-1 receptor antagonist (IL-1ra) locus modulate the risk of developing malignant lymphoma of a group of Iraqi patients in the Mid-Euphrates Sector, Iraq. Materials and Methods: A case-control study was conducted on 200 specimens obtained from patients with lymphoma and individuals without any apparent health conditions who served as the control group (considered normal individuals). The specimens were collected from various general hospitals and private clinics located in the Middle Euphrates region of Iraq. The study population included individuals aged between 17 and 75 years. Specimen collection took place between October 2022 and February 2023. Conventional polymerase chain reaction (PCR) was chosen for the detection of HHV-8 as well as IL-1ra gene polymorphism by sequencing. Results: According to PCR detection, 31 out of 64 (48.4%) of the specimens revealed PCR detection positivity for HHV-8, whereas 33 out of 64 (51.6%) specimens showed negative detection for HHV-8. The lymphoma which were most HHV-8-infected are related to the age stratum (56–75 years), accounted for 48%, whereas the age strata 15–35 years, and 36–55 years, each accounted for 23% and 29%, respectively. Conclusion: In view of the relatively small numbers included in our study, the present results indicate the possibility that HHV-8 and IL-1ra polymorphism may play a role in the tumor biology of lymphocyte and may contribute to their development.

IL-1ra polymorphisms and risk of epidural-related maternal fever (EPIFEVER-2): study protocol for a multicentre, observational mechanistic cohort study

BackgroundLaboratory data suggest that insufficient circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural-related maternal fever, both of which increase the rate of obstetric interventions and antibiotic use during labour. Genetic polymorphisms strongly influence IL-1ra levels in the general population. We aim to examine the association between IL-1ra polymorphisms and epidural-related maternal fever using Mendelian randomization analysis. MethodsEPIFEVER-2 is a multicentre UK trial enrolling 637 women receiving epidural analgesia for labour. Blood samples obtained no later than four hours after epidural insertion will provide deoxyribonucleic acid for Taqman single-nucleotide polymorphism genotyping for presence/absence of rs6743376, rs1542176 alleles for IL-1ra, to establish the genetic score. The absence of both alleles is associated with the lowest IL-1ra levels. The primary outcome is pyrexia (>38°C) or intrapartum antibiotic administration. Secondary outcomes include mode of delivery, maternal and neonatal healthcare interventions. ResultsThe EPIFEVER-2 study was prospectively registered (ISRCTN99641204) following ethical approval. Participant recruitment began in May 2021, with 221 women recruited across three centres as of November 21, 2021. ConclusionsEPIFEVER-2 will generate the largest prospective dataset detailing the incidence and consequences of epidural-related maternal fever. Using Mendelian randomisation analysis, a causative role for lower IL1-ra levels in determining the risk of epidural-related maternal fever and/or antibiotic administration before delivery will be examined.

Polymorphism of interleukin-1β and interleukin-1 receptor antagonist genes in children with autism spectrum disorders

In this study, we first investigated interleukin-1 beta (IL-1β) and IL-1 receptor antagonist (IL-1RA) levels in a cohort of Egyptian children with autism spectrum disorder (ASD) and in healthy controls. Second, we examined the single-nucleotide polymorphisms (SNPs) at positions −31 and − 511 of the IL-1β gene promoter and IL1RA and assessed the association between IL1B and IL1RA polymorphisms with ASD. We examined IL1β promoter polymorphism at −511 (IL-1β-511) and − 31 (IL-1β-31) and IL1RA gene polymorphism in 80 children with ASD and 60 healthy children. The children with ASD had significantly higher levels of IL-1β and IL-1RA than the controls. The children with ASD also had significantly higher frequencies of homozygous (CC) and heterozygous (TC) genotype variants of IL-1β-511, and IL-1RA than the controls. Moreover, the frequency of the IL-1β-511 allele (C) was higher in the ASD group than in the controls (p = .001). The homozygous and heterozygous variants of IL-1RA allele II were also significantly higher in the ASD group than in the control group. There was no significant association between the IL-1β-31 genotype and autism classes. However, there were significant differences in the distribution of the IL-1RA heterogeneous genotype and allele II among children with severe autism. The inflammatory role of cytokines has been implicated in a variety of neuropsychiatric pathologies, including autism. Our data show alterations in the IL-1β system, with abnormally increased serum levels of IL-1β and IL-1RA in the children with ASD. Further, polymorphisms in the IL-1β-511 and IL-1RA genotype variants correlated positively with autism severity and behavioral abnormalities. IL-1β-511 and IL-1RA gene polymorphisms could impact ASD risk and may be used as potential biomarkers of ASD. Variations in the IL-1β and IL-1RA systems may have a role in the pathophysiology of ASD.

Interleukin-1B (IL-1B-31andIL-1B-511) and interleukin-1 receptor antagonist (IL-1Ra) gene polymorphisms in primary immune thrombocytopenia

BackgroundImmune thrombocytopenia (ITP) is an immune-mediated disease caused by autoantibodies against platelets membrane glycoproteins GPIIb/IIIa and GPIb/IX. The etiology of ITP remains unclear. This study evaluated the association of polymorphisms in interleukin (IL)-1B-31, IL-1B-511, and IL-1Ra with ITP.MethodsGenotyping of IL-1B-31, IL-1B-511, and IL-1Ra was performed in 118 ITP patients and 100 controls by polymerase chain reaction restriction fragment length polymorphism and detection of variable number tandem repeats.ResultsGenotype differences in IL-1B-31 and IL-1Ra were significantly associated with ITP. Patients showed a higher frequency of the IL-1B-31 variant allele (T) and a 1.52-fold greater risk of susceptibility to ITP (odds ratio [OR]=1.52, 95% confidence interval [CI]=1.04–2.22, P=0.034). The frequencies of both homozygous and heterozygous variant genotypes of IL-1B-31 were higher (OR=2.33, 95% CI=1.069–5.09, P=0.033 and OR=2.044, 95% CI=1.068–39, P=0.034) among patients and were significantly associated with ITP susceptibility. Both homozygous and heterozygous variant genotypes of IL-1Ra were also more frequent (OR=4.48, 95% CI=1.17–17.05, P=0.0230 and OR=1.80, 95% CI=1.03–3.14, P=0.0494) among patients and were associated with ITP risk. IL-1B-31 and IL-1Ra also showed significant association with severe ITP. However, IL-1B-511 was not associated with ITP.ConclusionIL-1B-31 and IL-1Ra polymorphisms may significantly impact ITP risk, and they could be associated with disease severity, which may contribute to the pathogenesis of ITP.

Interleukin-1 receptor antagonist gene polymorphism and obesity a pilot study from Egypt.

The main adverse consequences of excess bodyweight are cardiovascular disease, type II diabetes, and several cancers. IL-1Ra serum concentration has been reported earlier to increase in human obesity and it is therefore assumed that the polymorphism of IL-1Ra may influence cytokine production. The study was designed to investigate whether the IL-1Ra polymorphism was associated with obesity. A total number of 66 individuals; 20 normal (BMI <25 Kg/m2), 20 overweight (BMI 25-29.9 Kg/m2) and 26 obese (BMI More than 30.0 Kg/m2) were enrolled in this study. Genotyping was performed using a polymerase chain reaction PCR amplification of the intron-2 fragment harboring a variable number of tandem repeat (VNTR) nucleotide sequences 86 bp of tandem repeat. The PCR products were separated on 2% agarose gel. Statistical analysis was performed using SPSS software (version 11.5). The genotype and allelic frequencies showed a significantly difference between normal vs. overweight and normal vs. obese (p-values: 0.001; 0.0001; 0.0018 and 0.001 respectively). Although, The presence of Allelic frequencies for Allele I between normal vs. overweight and normal vs. obese showed > 2 folds risk in overweight and >3 folds in obese (OR=2.3; 95% CI=0.796-8.620 & OR=2.1; 95% CI=0.972-10.265 respectively). Allele II between normal vs. overweight and normal vs. obese showed > 3.5 folds risk in overweight and >1.5 folds in obese (OR=3.45; 95% CI=0.836-9.210 & OR=1.63; 95% CI=0.892-9.11 respectively) and Allele V between normal vs. overweight and normal vs. obese showed > 2 folds risk in overweight and >1.5 folds in obese (OR=1.99; 95% CI=0.821-9.10 & OR=1.95; 95% CI=0.882-8.975 respectively).This may suggest that IL-1Ra appears to be induced by inflammatory stimuli as well as obesity-associated factors. This is relatively a pilot study; but nevertheless, may assist in identifying the pathophysiological cause for obesity

Cytokine gene polymorphism [tumor necrosis factor-alpha (-308), IL-10 (-1082), IL-6 (-174), IL-17F, 1RaVNTR] in pediatric patients with primary immune thrombocytopenia and response to different treatment modalities.

To evaluate the association between development, progression, and response to therapy among patients with immune thrombocytopenia (ITP) and different cytokine gene polymorphisms known to be related to autoimmunity [tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, IL-6, IL-17, IL-1Ra]. A total of 50 pediatric patients with ITP (20 newly diagnosed, 30 chronic) and 50 healthy controls were investigated via PCR-restriction fragment length polymorphism analysis for cytokine gene polymorphism. Compared with controls, all patients showed a higher frequency of IL-6-174 CC [P = 0.0001, odds ratio (OR) = 7.048, 95% confidence interval (CI) = 2.18-22.7], higher GA genotype of TNF-α (-308) (P = 0.001, OR = 6.469, 95% CI = 2.0-20.9), higher CC genotype of IL-17F (P = 0.0001, OR = 55.545, 95% CI = 14.4-213.2), higher GG of IL-10-1082 (P = 0.029, OR = 3.6, 95% CI = 1.08-12.18), and A1A2 genotype of IL-1Ra (P = 0.039, OR = 2.374, 95% CI = 1.03-5.4). IL-10 GA and IL-1Ra A1A1 genotypes were higher among chronic patients (P = 0.042, P = 0.001 respectively) compared with newly diagnosed ones. Best platelet response to steroid treatment was found among GC genotype of IL-6 (-174) and GG genotype of IL-10 (-1082) in all patients with ITP. This suggests that previously mentioned cytokine gene polymorphisms possibly contribute to the susceptibility of acquisition of childhood ITP. Furthermore, GA genotype of IL-10 and A1A1 genotype of IL-1Ra polymorphisms are associated with increased risk of chronic ITP. IL-6 (-174) and IL-10 (-1082) genes might play a role in the effectiveness of steroid therapy among patients with ITP.

DNA methyltransferase 3B gene promotor and interleukin-1 receptor antagonist polymorphisms in Egyptian children with immune thrombocytopenic purpura

Background and objectives Idiopathic thrombocytopenic purpura (ITP) is an autoimmune condition characterized by increased platelet destruction. Although the etiology of ITP remains unclear, it is accepted that both environmental and genetic factors play an important role in the development of the disease. Many gene polymorphisms have been reported to be closely associated with the susceptibility to ITP. Aim of the work The current study aimed to investigate the association between the DNA methyltransferase DNMT3B-46359 C/T promoter and IL-1Ra polymorphism and the risk for acquisition of pediatric ITP in a cohort of Egyptian children. Patients and methods Genotyping of the studied genes using PCR-RFLP assays was conducted on 40 children with ITP and 20 age-matched and sex-matched normal controls. Results Our results revealed that DNMT3B-46359 C/T heterotype was higher in patients than in controls but did not reach statistical significance and conferred 2.2-fold increased risk for ITP (odds ratio=2.2, confidence interval = 1.4–2.6). There was no statistically significant difference between ITP patients and controls as regards allele frequency. Moreover, there was no statistically significant difference in the clinical and laboratory data between ITP patients with wild or mutant genotypes. Moreover, there was no statistically significant difference in the distribution of DNMT3B-46359 . C/T genotypes between acute and chronic ITP patients. Conclusion This genetic polymorphism cannot be considered as a molecular marker for ITP risk among Egyptian children. Moreover, it is not a molecular predictor for chronicity.

Association of interleukin-1 gene cluster polymorphisms and haplotypes with multiple sclerosis in an Iranian population

Multiple sclerosis (MS) is a multi-factorial autoimmune disease of the central nervous system. The exact etiology of MS is still unknown. Due to the important roles that cytokines play as mediators in immune and inflammatory responses, we have evaluated the association of IL-1 gene cluster polymorphisms and haplotypes with MS susceptibility in 306 unrelated MS patients and 312 healthy matched controls. A significant association was found for the IL-1β +3953 T allele [OR=1.43, 95% CI (1.14–1.79), P value=0.002, Pc=0.01] and for IL-1β +3953 T/T genotype and MS risk [OR=1.92, 95% CI (1.25–2.96), P value=0.005, Pc=0.01]. Interestingly, the genotypes of the polymorphisms remained significant under recessive, co-recessive and dominant models. However, no significant differences were found between MS patients and controls in the genotype and allele frequencies of the IL-1β −511, −31 and IL-1Ra polymorphisms. Haplotype analysis for IL-1β −31 and IL-1β −511, with moderate linkage disequilibrium (LD), using the EM algorithm revealed a significant global association of haplotype differences between the two groups. Lower presence of two haplotypes (H3: C-T and H4: T-C) was observed in the MS patients than healthy controls. However, after applying Bonferroni's correction the differences were not significant. To our knowledge, this is the first study reporting the association of the IL-1β +3953 gene polymorphism and MS susceptibility.

Association between polymorphism of interleukin-1 beta and interleukin-1 receptor antagonist gene and asthma risk: a meta-analysis.

Background. Asthma is a complex polygenic disease in which gene-environment interactions are important. A number of studies have investigated the polymorphism of IL-1β -511C/T and IL-1RA genes in relation to asthma susceptibility in different populations. However, the results of individual studies have been inconsistent. Accordingly, we conducted a comprehensive meta-analysis to investigate the association between the IL-1β -511C/T and IL-1RA polymorphism and asthma risk. Methods. Data were collected from the following electronic databases: Pub Med, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), ISI Web of Knowledge, and Google Scholar Search databases with the last report up to July 2013. Finally, 15 studies were included in our meta-analysis. We summarized the data on the association between IL-1β -511C/T and IL-1RA polymorphism and risk of asthma in the overall population and performed subgroup analyses by ethnicity, mean of age, and source of controls. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the associations between IL-1β -511C/T and IL-1RA polymorphism and asthma risk. Statistical analysis was performed with Review Manager 5.1. Results. A total of 15 case-control studies were included in the meta-analysis of IL-1β -511C/T (1,385 cases and 1,964 controls) and IL-1RA (2,800 cases and 6,359 controls) genotypes. No association was found between IL-1β -511C/T polymorphism and asthma risk (dominant model: OR = 1.11, 95% CI: 0.99–1.25, P = 0.07, P Heterogeneity = 0.06; recessive model: OR = 1.04, 95% CI: 0.91–1.20, P = 0.55, P Heterogeneity = 0.11). Subgroup analysis based on ethnicity (Asian and Caucasian), source of controls (population-based controls and hospital-based controls), and mean of age (adulthood and childhood) did not present any significant association. The overall results showed that the IL-1RA polymorphism was related to an increased risk of asthma (homozygote model: OR = 1.32, 95% CI: 1.12–1.56, P = 0.0009, P Heterogeneity = 0.87; recessive model: OR = 1.39, 95% CI: 1.18–1.63, P = 0.0001, P Heterogeneity = 0.82). Similar results were found in the subgroup analyses by ethnicity, mean of age, and source of controls. Sensitivity analysis did not perturb the results. Conclusions. This meta-analysis provided strong evidence that the IL-1RA polymorphism was a risk factor of asthma, especially in Caucasian populations. However, no association was found for IL-1β -511C/T genotype carriers. Larger scale studies are needed for confirmation.

Significance of IL-1RA Polymorphism in Iranian Patients with Inflammatory Bowel Disease.

Interleukin (IL)-1 family members play an important role in the pathogenesis of inflammatory bowel disease (IBD). There are conflicting results regarding the association of IL-1 gene cluster single nucleotide polymorphisms (SNPs) with IBD and its clinical features. The aim of this study was to examine IL-1α -889 C/T, IL-1β -511 C/T, IL-1β +3962 C/T, IL-1R Pst-I1970 C/T, and IL-1RA Mspa-I11100 C/T SNPs in Iranian patients. In this study, SNPs of IL-1 family members were investigated in 75 patients with IBD (40 CD and 35 UC), using polymerase chain reaction with sequence-specific primers method. IL-1β -511 CC genotype was significantly less present in UC compared to controls, while IL-1RA Mspa-I11100 CC was significantly associated with both Crohn's disease (CD) and ulcerative colitis (UC). IL-1α -889 TT genotype was more frequently associated with extraintestinal manifestations. A significant association was observed between IL-1β +3962 TT genotype and the disease activity in IBD. IL-1RA Mspa-I11100 CC was significantly less frequent in CD patients who need immunosuppressive therapy. IL-1RA Mspa-I11100 CT was associated with earlier age of onset in IBD, while TT genotype was associated with higher age of onset in IBD. IL-1 SNPs seem to be associated with IBD and could affect the disease severity as well.

Associations between IL-1RA polymorphisms and small intestinal bacterial overgrowth among patients with irritable bowel syndrome from India.

Low-grade inflammation (controlled by pro and anti-inflammatory molecules), induced by gut microbes in patients with small intestinal bacterial overgrowth (SIBO), may be associated with irritable bowel syndrome (IBS). Polymorphisms of IL-RA gene (anti-inflammatory) was evaluated in IBS and healthy subjects (HS); small intestinal mucosal IL-1α and β levels (pro-inflammatory) in relation to the presence of SIBO were evaluated in a subset of patients. Two hundred and twenty-one IBS patients and 273 age- and gender-matched HS were included. Exactly 209 of 221 patients (Rome III) and 273 HS were genotyped (PCR) for IL-1RA polymorphism. Mucosal IL-1α and β levels (pg/mg of biopsy) were estimated (ELISA) in 82/221 patients with and without SIBO (≥10(5) CFU/mL upper gut aspirate bacteria). Genotype 1/1 (IL-1RA over-producer) was less frequent among patients than controls (p=0.007); genotypes 1/3 (p=0.012, OR=3.301, 95% CI=1.31-8.35) and 2/3 (both under-producers; p=0.009, OR=7.703, 95% CI=1.66-35.82) were commoner among IBS. Fifteen of 82 (18.3%) patients had SIBO. Levels of IL-1α and β were higher among patients with SIBO than without (IL-1α: 35.4 [20.1-66.8] vs 25.5 [4.2-65.3], p<0.001; IL-1β: 206.8 [133.5-365.9] vs 93.1 [25.5-197.7], p<0.001) and those with bloating than without (p=0.012; p=0.015). IL-1β was higher among patients with Bristol stool type 6 than those with type 1-2 (p=0.002) and type 3-5 (p=0.007). Polymorphisms 1/1 (IL-1RA over-producer) was infrequent and 1/3 and 2/3 (under-producers) frequent among IBS. Increased IL-1α and β levels were associated with SIBO. Increased IL-1β level was predominantly associated with bloating and loose stools (Bristol type 6).

A Candidate Gene Approach to ANCA-Associated Vasculitis Reveals Links to the C3 and CTLA-4 Genes but not to the IL1-Ra And Fcγ-RIIa Genes

Background/Aims: The aim of the study is to search for associations between Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and polymorphisms in the genes of four key molecules possibly involved in different pathogenic pathways; complement C3, CTLA-4, Fcγ-RIIa and IL1-Ra. Patients and Methods: Patients with AAV (n=105) subgrouped as microscopic polyangiitis or granulomatosis with polyangiitis (Wegener's granulomatosis) and myeloperoxidase (MPO) or proteinase 3 (PR3) ANCA positive were compared to a control group of 200 blood donors. Polymorphisms in the genes were analysed with PCR amplification of DNA. Results: The diagnosis of AAV was confirmed in the 105 cases. The gene frequency of C3F was 0.27 in the PR3-ANCA subgroup (p=0.041) compared to 0,19 in the control group. The number of patients homozygous for the shortest 86 bp allele of CTLA-4 was significantly decreased in the whole group of patients (p=0.049). No differences were evident in the Fcγ-RIIa and IL1-Ra polymorphisms when compared to controls, neither in the whole group of patients, nor in any of the sub-groups. Conclusion: The aberrant gene frequency of the C3F allele among PR3-ANCA positive patients and the findings with the CTLA-4 polymorphism indicates that complement may be involved in pathogenesis and that T-cell activation also is of importance in these diseases.

TNF-α and IL-1RA Polymorphisms and Silicosis Susceptibility in Chinese Workers Exposed to Silica Particles: A Case-Control Study

ObjectiveTo assess the association of TNF-α and IL-1RA SNPs with the risk of silicosis in Chinese workers exposed to silica particles. MethodsCase-control study design was used to enroll 68 silicotic patients induced by silica particles and 68 healthy workers matched for length of silica particle exposure as controls. Both cases and controls were from the same company in southwest China, and each of them was requested to complete a questionnaire. Blood samples were drawn for genomic DNA extraction from each participant. The genotyping of TNF-α (−238 and −308) and IL-1RA (+2018) was performed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) and SYBR green-based quantitative polymerase chain reaction (qPCR), respectively. Unconditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidential intervals (CI) for SNPs. ResultsNo significant differences were found between cases and controls in particles exposure length, body mass index (BMI), and status of smoking and alcohol consumption except for age (P=0.001) and blood type (P=0.042). The frequencies of TNF-α (−238) and IL-1RA (+2018) genotypes in cases were significantly different from those in controls, (P=0.001 and P=0.002, respectively), while a borderline significant difference was found in the frequencies of TNF-α (−308) between cases and controls (P=0.063). The variants of three SNPs increased the risk of silicosis in the Chinese workers exposed to silica particles. The adjusted ORs of TNF-α (−308), TNF-α (−238) and IL-1RA (+2018) were 2.8 (95% CI: 1.1–7.5), 20.9 (95% CI: 1.8–236.4) and 4.0 (95% CI: 1.6–10.1), respectively. ConclusionIt is suggested that cytokine polymorphisms of TNF-α (−238, −308) and IL-1RA (+2018) are associated with the risk of silicosis in the Chinese workers exposed to silica particles. Further independent studies on the interaction between SNPs and exposure to silica particles with a larger sample size are therefore warranted.

Interleukin-1 receptor antagonist gene polymorphism in patients with multidrug-resistant Acinetobacter baumannii-associated pneumonia

OBJECTIVE:Multidrug-resistant Acinetobacter baumannii (MDRAB)-associated pneumonia has been a common disease and a therapeutic problem in hospitals. Interleukin-1 receptor antagonist (IL-1ra) has been considered a required role for host immune defense in pneumonia disease. The aim of this study was to investigate whether the variable nucleotide tandem repeat polymorphism of the IL-1ra gene was associated with MDRAB-related pneumonia.METHODS:Sixty-six pneumonia patients were enrolled in the study: 36 subjects had MDRAB-related pneumonia and 30 controls had non-MDRAB pneumonia. Polymerase chain reaction, restriction fragment length polymorphism, and agarose gel electrophoresis techniques were used to determine the IL-1ra genotype.RESULTS:The frequencies of the IL-1ra genotype in the MDRAB-related pneumonia cases were A1/A1, 0.889 and A1/A2, 0.111; the frequencies of the IL-1ra genotype in the controls were A1/A1, 0.333 and A1/A2, 0.667. A statistically significant difference was determined (P < 0.05). We also observed an increase in the frequency of IL-1ra A1 allele in the MDRAB-related pneumonia group. A statistically significant difference was determined (P<0.05).CONCLUSIONS:We suggested that IL-1ra polymorphism was associated with the risk of MDRAB-related pneumonia.

Polymorphismes des cytokines pro-inflammatoires (TNFα et IL1) au cours de l’asthme allergique

Introduction TNFα and IL1 are two inflammatory cytokines involved in the late inflammatory stage of asthma. Aim We aimed to detect genetic polymorphisms of those two cytokines which can modify the rate of their expression and thus influence the disease predisposition and its clinical outcome. Patients and methods Polymorphisms of TNFα (G/A-308), IL1β (C/T –511), IL1β (C/T +3954), IL1α (C/T –889) and IL1Ra (intron 2) were analyzed by polymerase chain reaction in 107 patients with asthma and 168 controls. Results The frequency of the allele T of IL1β (C/T +3954) was significantly lower in patients than in controls ( P = 0.002; OR: = 0.423; CI: [0.239–0.746]) while the homozygous genotype IL1Ra*2/2 was significantly more frequent in patients comparatively to controls ( P = 0.0056; OR: = 11.57; CI: [1.4–25.44]). There were no significant differences in genotypic and allelic frequencies in polymorphisms of TNFα (G/A -308), IL1α (C/T –889) and IL1β (C/T –511) between patients and controls. IL1Ra*2 allele was significantly more frequent in patients with high levels of IgE (> 200 UI/mL) (25%) comparatively to patients with normal levels (16.7%) P = 0.031; OR: = 3.5; CI: [1.064–11.5]. Nevertheless, adjustments for known covariates factors (age and gender) had not confirmed these univariate findings. Conclusion In Tunisia, IL1Ra polymorphism seems to predispose to asthma while the IL1β (C/T +3954) is rather protecting.

Association of interleukin-1 beta (-511C/T) polymorphisms with osteoporosis in postmenopausal women

BACKGROUND AND OBJECTIVES:Osteoporosis is a common disease of the elderly, in which genetic and clinical factors contribute to the disease phenotype. Since the production of interleukin-1 (IL-1) has been implicated in the bone mass and skeletal disorders, we investigated whether IL-1 system gene polymorphisms are associated with the pathogenesis of osteoporosis in postmenopausal Taiwanese women.METHODS:Osteoporosis is diagnosed by dual-energy x-ray absorptiometry, which measures bone mineral density (BMD) at multiple skeletal sites. We studied the IL-1α (-889C/T), IL-1β (-511C/T) and the 86 base pair variable number tandem repeat (VNTR) in intron 2 of the IL-1 receptor antagonist (IL-1ra) gene in 117 postmenopausal women with osteoporosis and 135 control subjects without a history of symptomatic osteoporosis. These gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymerase. Blood sugar and other risk factors were also determined.RESULTS:The frequencies of IL-1β (-511C/T) genotypes (P=.022, odds ratio=1.972) and alleles (P=.02, odds ratio=2.909) showed a statistically significant difference between the two groups. However, we did not find any statistically significant difference in IL-1α and IL-1ra polymorphisms (P>.05). We also observed a positive relationship between osteoporosis and cholesterol and a weak inverse relationship between blood sugar and osteoporosis in postmenopausal women.CONCLUSIONS:These experimental results suggest that the pathogenesis of osteoporosis is associated with IL-1β (-511C/T) polymorphism in postmenopausal women. This polymorphism is an independent risk factor for osteoporosis.

Interleukin 1 receptor antagonist polymorphisms are associated with the risk of developing acute coronary syndrome in Mexicans

Inflammation plays an essential role in the development and progression of atherosclerotic lesions. Cytokines of the interleukin-1 family are central regulators in immunoinflammatory mechanisms. In the present work, the role of interleukin 1 ( IL-1) and IL-1 receptor antagonist ( IL-1RN) gene polymorphisms as susceptibility markers for acute coronary syndrome (ACS) was evaluated. Six polymorphisms in the IL-1 gene cluster members were genotyped by 5′ exonuclease TaqMan genotyping assays in 289 ACS patients and 248 healthy controls. Haplotypes were constructed after linkage disequilibrium analysis. Statistically significant associations were found between three polymorphisms of the IL-1RA gene (rs419598, rs315951, and rs2234663) and the development ACS. The polymorphism RN.4T> C (rs419598) was associated with hypertension, previous myocardial infarction, and major adverse cardiac events. To establish the functional effect of the IL-1RN6/ 2 (rs315951) polymorphism (principal IL-1RN polymorphism associated with ACS in our study), monocytes were obtained from a group of 27 healthy individuals and the production of IL-1 receptor antagonist (IL-1Ra) was determined. Monocytes from individuals with rs315951 CC genotype showed similar production of IL-1Ra as individuals with GG and CG genotypes. The analysis of linkage disequilibrium of the IL-1RA polymorphisms showed four out of eight different possible allele combinations with differences between the studied groups. Patients with ACS showed increased frequency of “ T1C” haplotype when compared to healthy controls. The results suggest that IL-1RN gene polymorphisms could be involved in the risk of developing ACS in Mexican individuals.

A Functional Interleukin-1 Receptor Antagonist Polymorphism Influences Atherosclerosis Development The Interleukin-1.BETA.:Interleukin-1 Receptor Antagonist Balance in Atherosclerosis

Interleukin (IL)-beta plays a central role in inflammation and atherosclerosis, but levels of IL-1beta, its natural antagonist, IL-1Ra, and their balance in human atherosclerotic lesions, are unknown. Knowledge of protein levels in atherosclerosis and the influence of a functional IL-1Ra polymorphism would increase the understanding of atherosclerosis pathogenesis. Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1beta, IL-1Ra and IL-1 receptor 1 (IL-1R1) using TaqMan PCR and enzyme-linked immunosorbent assay. Two hundred forty-three survivors of a first myocardial infarction were genotyped for a polymorphism in IL-1Ra and their coronary atherosclerosis analyzed by using coronary angiography. Levels of IL-1beta, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1beta levels more than IL-1Ra levels (ie, promoted a pro-inflammatory state). A polymorphism in IL-1Ra known to increase levels of IL-1Ra was associated with decreased mean coronary artery plaque area. Activation of innate immunity changed the balance between IL-1beta and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this, the presence of an IL-1Ra intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1beta ratio, was associated with reduced coronary atherosclerosis.

Gene polymorphisms of IL-6−174 G/C and IL-1Ra VNTR in asthmatic children

To check for the association of genetic polymorphisms of IL-6-(-174)G/C and IL-1RaVNTR with the susceptibility and severity of asthma in Egyptian children. Subjects included 69 asthmatic children and 98 healthy unrelated controls from the Nile Delta of Egypt. Cases consisted of 20 males and 49 females with an age mean +/- SD is 7.5 +/- 2.1 ranging between 2-13 years. DNA amplification using PCR with sequence-specific primers was done for detection of promotor single nucleotide polymorphism of IL-6 gene as well as intron 2 VNTR of IL-1Ra gene. Frequency of case-genotypes or alleles were compared to controls using Fisher exact test and Odds ratio. Cases showed significant higher frequency of the genotypes: IL-6-174 GG (P<0.05, OR=3.2, 95% CI=1.09-10) that was evident mainly in the uncontrolled asthma subgroup indicative of the possibility of being a severity genotype. All cases as well as case-subgroups showed high significant frequency of IL-1Ra A1A1 (p<0.0001, OR=1.5, 95% CI=1.3-1.8). This may be considered a susceptibility genotype. Cases have also shown significant lower frequency of IL-6(-174) GC and IL-1Ra A1A2 genotypes (P<0.001 and P<0.0001 respectively). IL-6 and IL-1Ra polymorphisms can be considered genetic markers for bronchial asthma susceptibility and/or severity among Egyptian children. This may have a potential impact on family counseling and management.