IL-1RN VNTR Research Articles

An interleukin-1 polymorphism additionally intensified by atopy as prognostic factor for aseptic non-mechanical complications in metal knee and hip arthroplasty.

In contrast to infection or mechanical issues joint replacement failure following inflammatory adverse reactions is poorly understood. To assess the association of IL-1β polymorphisms and history of allergy with aseptic non-mechanical complications following arthroplasty. In 102 patients with aseptic non-mechanically caused symptomatic knee or hip arthroplasty (SA) and 93 patients with asymptomatic arthroplasty (AA) questionnaire-based history, patch test with at least standard series, lymphocyte transformation test (LTT) with nickel, cobalt and chromium and interleukin-1 polymorphism analysis were done. Three polymorphisms of the IL1B gene [IL-1b -3954 (rs1143634), IL-1b -511 (rs16944) and IL-1b -31 (rs1143627)] and one polymorphism of the IL1RN gene [IL1RN intron 2, variable number of tandem repeats, VNTR (rs2234663)] were assessed by PCR and gel electrophoresis. We found no significant difference in smoking history and atopy but 25% versus 10% of self-reported metal allergy in SA versus AA; the patch test (respective, LTT) for metal sensitivity was more often positive in SA patients. The allele 498 bp of the IL1RN polymorphism occurred significantly more often in the SA group (37% versus 11%; p < 0.0001). Upon additional presence of atopy, the difference was even greater (60% vs 10%) (p < 0.000001). There was no association of IL-1 polymorphisms with metal allergy. The IL1RN VNTR allele 498 bp was strongly associated with SA. In patients with a history of atopy, presence of the IL1RN VNTR allele 498 bp led to a four-fold higher SA prevalence compared to patients without this allele.

Genetic Polymorphisms Associated with Perioperative Joint Infection following Total Joint Arthroplasty: A Systematic Review and Meta-Analysis.

The number of orthopedic procedures, especially prosthesis implantation, continues to increase annually, making it imperative to understand the risks of perioperative complications. These risks include a variety of patient-specific factors, including genetic profiles. This review assessed the current literature for associations between patient-specific genetic risk factors and perioperative infection. The PRISMA guidelines were used to conduct a literature review using the PubMed and Cochrane databases. Following title and abstract review and full-text screening, eight articles remained to be reviewed—all of which compared single nucleotide polymorphisms (SNPs) to periprosthetic joint infection (PJI) in total joint arthroplasty (TJA). The following cytokine-related genes were found to have polymorphisms associated with PJI: TNFα (p < 0.006), IL-6 (p < 0.035), GCSF3R (p < 0.02), IL-1 RN-VNTR (p = 0.002), and IL-1B (p = 0.037). Protein- and enzyme-related genes that were found to be associated with PJI included: MBL (p < 0.01, p < 0.05) and MBL2 (p < 0.01, p < 0.016). The only receptor-related gene found to be associated with PJI was VDR (p < 0.007, p < 0.028). This review compiled a variety of genetic polymorphisms that were associated with periprosthetic joint infections. However, the power of these studies is low. More research must be conducted to further understand the genetic risk factors for this serious outcome.

PB1967: ROLE OF CYTOKINES IN MULTIPLE MYELOMA: IL-1RN AND IL-4 VNTR POLYMORPHISMS

Background: Cytokines have important effects on immune regulation and oncogenesis. IL-1 is a cytokine with important physiological roles in cytokine regulation, vascular permeability and sepsis in autoimmune diseases. The IL-1 receptor antagonist (IL-1Ra or IL-1RN) is a member of the IL-1 superfamily that functions as a competitive antagonist of the cell surface IL-1 receptor, thereby regulating various immune and inflammatory responses related to IL-1. IL-1 induces tumor growth and metastasis, while IL-1RN inhibits the secretion of IL-1α and IL-6 in cancer cells. Interleukin-4 (IL-4) is a potent anti-inflammatory cytokine, and its gene is located on the long arm of chromosome 5 (q23-31) along with other cytokine genes. IL-4 can be secreted by many types of immune cells, including basophils, eosinophils, myeloid lineage cells, mast cells, and activated T cells. Aims: In this study, it was aimed to reveal the effects of IL-1RN and IL-4 VNTR polymorphisms on disease development and survival in patients with MM. Methods: In this study, 244 patients diagnosed with MM in hematology clinic between January 2010 and January 2021, and 179 healthy individuals were included. The control group did not have any kind of cancers and consisted of a unrelative population permanently residing in Turkey. ASCT was performed for 73% of the patients after 4 courses of VCD (bortezomib, cyclophosphamide, and dexamethasone) with at least a partial remission and then LD (lenalidomide and dexamethasone) was used as a maintenance therapy for the following follow-up period. The 1/1, 1/2, 1/3, 1/4, 2/2, 2/3 and 2/4 genotypes of the IL-1RN VNTR polymorphism were statistically compared before treatment between patients having undergone ASCT and healthy controls, as were the 1/1, 1/2 and 2/2 genotypes of IL-4 VNTR polymorphism. Additionally, the statistically significant effects of these genotypes on survival were examined. Results: The median age of 244 patients included in the study was 58 old years (range: 29-81). The 5-year and 10-year OS were 76% and 53%. The 5-year and 10-year PFS were 42% and 21%, respectively. The median PFS was 42,3 months. The median follow-up period was 27 months (4,4-155 months). In the statistical analysis of the distribution of IL-1RN VNTR gene variants, 1/3 and 1/4 genotypes were found to be significantly higher in patients with MM compared to the healthy controls (p=0,035). In the statistical analysis of the distribution of IL-4 VNTR gene variants, there was no significant difference between the MM patient group and the healthy controls in terms of genotype distribution (p>0.05, for all). IL-4 VNTR genotype distribution did not have a significant effect on PFS and OS. PFS of patients with IL-1RN VNTR non-2-allele carrier genotypes was significantly shorter, but no significant effect was found on OS (p=0,03, p=0,786, respectively. Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1,718-fold increased risk of shorter PFS. Image:Summary/Conclusion: In conclusion, with this study, the effects of IL-1RN VNTR and IL-4 VNTR polymorphisms on MM were evaluated for the first time in the literature. The IL-1RN 1/3 and 1/4 genotypes were significantly more common in patients with MM compared to healthy controls. Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1,718-fold increased risk of shorter PFS, but no significant effect on OS was demonstrated. IL-4 polymorphism, on the other hand, did not have a significant effect on MM development or survival. This study will shed light on ones on cytokine-MM relationship and epigenetic mechanisms.

Role of cytokines in multiple myeloma: IL-1RN and IL-4 VNTR polymorphisms

IntroductionThe IL-1 receptor antagonist (IL-1Ra or IL-1RN) is a member of the IL-1 superfamily that functions as a competitive antagonist of the cell surface IL-1 receptor, thereby regulating various immune and inflammatory responses related to IL-1. IL-1 induces tumor growth and metastasis, while IL-1RN inhibits the secretion of IL-1α and IL-6 in cancer cells. Interleukin-4 (IL-4) is a potent anti-inflammatory cytokine, can be secreted by many types of immune cells. In this study, it was aimed to reveal the effects of IL-1RN and IL-4 VNTR polymorphisms on disease development and survival in patients with multiple myeloma (MM). Material and methodsIn this study, 244 patients diagnosed with MM in hematology clinic between January 2010 and January 2021, and 179 healthy individuals were included. The genotypes of the IL-1RN VNTR polymorphism were statistically compared before treatment between patients having undergone stem cell transplantation and healthy controls, as were the genotypes of IL-4 VNTR polymorphism. Additionally, the statistically significant effects of these genotypes on survival were examined. ResultsIn the statistical analysis of the distribution of IL-1RN VNTR gene variants, 1/3 and 1/4 genotypes were found to be significantly higher in patients with MM compared to the healthy controls (p = 0.035). There was no significant difference between the MM patient group and the healthy controls in terms of IL-4 VNTR genotype distribution. PFS of patients with IL-1RN VNTR non-2-allele carrier genotypes was significantly shorter, but no significant effect was found on OS (p = 0.03, p = 0.786, respectively). Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1.718-fold increased risk of shorter PFS. ConclusionsIn conclusion, with this study, the effects of IL-1RN VNTR and IL-4 VNTR polymorphisms on MM were evaluated for the first time in the literature. This study will shed light on ones on cytokine-MM relationship and epigenetic mechanisms.

Contribution of genetic polymorphisms of interleukins IL1B-511 C/T, IL1RN VNTR, IL6-174 G/C, and IL8-251 A/T in gastric lesions: gender and Helicobacter pylori genes matter.

Stomach pathologies develop in a complex interaction between the host's genetic background and H. pylori virulent genes. Thus, our study aimed to compare active chronic gastritis (ACG), and intestinal metaplasia (IM) with inactive chronic gastritis (ICG), according to interleukin polymorphisms of IL6-174 G/C, IL8-251 A/T, IL1β-511 C/T, and IL1RN VNTR taking into account patient gender and H. pylori genotypes. Interleukin polymorphisms were determined by RFLP-PCR and H. pylori genotype by PCR. IL6-174 GC and IL8-251T allele showed a protective effect in women against ACG development and, conversely, IL8-251 polymorphism showed a risk for men. More virulent H. pylori strains were associated with the IL8-251T allele and IL1β-511T allele in the AGC, and the vacA m1allele and cagE gene from H. pylori was associated with the IM. Analysis of the progression of gastric lesions must take into account host variability genetic associated with genes H. pylori due to the relation between the virulent H. pylori genes and more severe gastric lesions, besides the relevance to the gender to IL6-174 and IL8-251 polymorphisms.

The association between IL-1 family gene polymorphisms and colorectal cancer: A meta-analysis.

Colorectal cancer (CRC) is a major public health problem given its high incidence and mortality. This study focuses on examining the associations between IL-1α, IL-1β, and IL-1RN polymorphisms and colorectal cancer susceptibility. A systematic literature search of PubMed, Embase, Web of Science, CNKI (China National Knowledge Infrastructure) and Wan Fang databases was conducted to identify relevant studies. Relevant data were extracted from the original included studies. The correlation was demonstrated based on the odds ratio (OR) and corresponding 95% confidence intervals (95% CIs). Publication bias was investigated by Egger's line regression test and Begg's funnel plot. Eighteen independent studies involving 6218 cases and 10160 controls were eligible for this pooled analysis. Overall, the result revealed that the IL-1α rs3783553 polymorphism was significantly associated with an increased risk of CRC (G vs. C, OR=1.02, 95% CI=0.90-1.15, I2=51%, P=0.78; GG vs. CC, OR=1.97, 95% CI=1.04-3.74, I2=70%, P=0.04; GC vs. CC, OR=1.75, 95% CI=1.12-2.75, I2=42%, P=0.01; GG+GC vs. CC, OR=1.85, 95% CI=1.08-3.18, I2=63%, P=0.03; and GG vs. GC+CC, OR=1.28, 95% CI=1.04-1.58, I2=39%, P=0.02), and significance was also noted for IL-1RN VNTR under the dominant model (22+2L vs. LL, OR=1.49, 95% CI=1.01-2.19, I2=77%, P=0.045) and allelic contrast model (2 vs. L, OR=1.28, 95% CI=1.00-1.64, I2=58.6%, P=0.047). For IL-1β+31C/T, significance was observed in the dominant model (CC+CT vs. TT, OR=0.83, 95% CI=0.69-0.99, I2=52%, P=0.034) and the heterozygous model (CT vs. TT, OR=0.80, 95% CI=0.65-0.98, I2=60%, P=0.04). For IL-1β+511 C/T, a significant association was noted in four gene models (CT vs. TT, OR=0.72, 95% CI=0.63-0.83, I2=0%, P<0.001; CC+CT vs. TT, OR=0.74, 95% CI=0.65-0.84, I2=0%, P<0.001; CC vs. TT, OR=0.77, 95% CI=0.65-0.91, I2=30.9%, P=0.003; C vs. T, OR=0.87, 95% CI=0.80-0.95, I2=38%, P=0.001), but a significant relationship was not found in the recessive model (CC vs. CT+TT, OR=1.09, 95% CI=0.86-1.38, I2=57.1%, P=0.25). In addition, borderline statistical significance was noted between IL-1β+3954 Ins/Del and CRC in the homozygous model, but no significance was identified for IL-1β+3737 G/A, Il-1β+1464 G/C, and IL-1RN+2018T/C under all five genetic models. In the subgroup analysis of ethnic groups, significant associations with CRC were found for IL-1β+31 (CC vs. TT: OR=0.82, 95% CI=0.67-0.99, I2=20.2%, P=0.04; CT vs. TT: OR=0.62, 95% CI=0.47-0.82, I2=0%, P<0.001; CC+CT vs. TT: OR=0.69, 95% CI=0.55-0.87, I2=29.7%, P=0.001), IL-1β+511 (CT vs. TT, OR=0.65, 95% CI=0.55-0.77, I2=0%, P<0.001; CC+CT vs. TT, OR=0.67, 95% CI=0.58-0.78, I2=0%, P<0.001; C vs. T, OR=0.83, 95% CI=0.75-0.92, I2=49.6%, P<0.001) and IL-1RN+2018T/C in the allelic contrast model (T vs. C, OR=0.66, 95% CI=0.44-0.98, I2=0%, P=0.04) among Asians but not in Caucasians. A significant association between IL-1β+1464 G/C polymorphisms in Caucasians was observed under the recessive model (OR=0.87, 95% CI=0.77-0.98, I2=45%, P=0.03). The current meta-analysis demonstrated that IL-1α rs3783553, IL-1β+31C/T, IL-1β+511C/T, and IL-1RN VNTR are critical genes for CRC susceptibility.

Inflammation-associated gene polymorphisms and clinical variables in the incidence and progression of retinopathy of prematurity.

IntroductionA growing body of evidence shows that genetics plays a vital role in the development and progression of retinopathy of prematurity (ROP). Perinatal inflammation is also considered an important risk factor of ROP. Therefore, understanding the interplay of genetics and susceptibility to inflammation might shed light on the pathogenesis of ROP and make its screening and treatment more effective in preventing visual impairment in premature infants.Material and methodsThis study investigated the correlation of inflammation-associated gene polymorphisms: IL-1β +3953 C>T, IL-1RN VNTR 86 bp, IL-6 -174 G>C, IL-6 -596 G>A, and TNF-α -308 G>A as well as demographic and clinical characteristics of ROP in preterm infants (n = 90).ResultsOur results demonstrate that IL-1RN rs2234663 1/1 genotype prevails in infants with ROP that regresses without intervention, when compared to those requiring laser photocoagulation/anti-VEGF injection (p = 0.031). Genotype 2/2 of IL-1RN occurs more frequently in children with severe ROP (28.6%) than in the group in which ROP regressed spontaneously (4.0%). The analysis revealed also differences between the genotypes of IL-1RN in ROP patients with intrauterine infection and in patients who had ROP without intrauterine infection; however, this was not statistically significant. Other studied polymorphisms were not associated with ROP development or its progression.ConclusionsThese results suggest that different genotypes of IL-1RN might have an impact on the course of ROP. Genotype 2/2 of IL-1RN gene may predispose to ROP progression.

IL-1RN VNTR, IL-2(-330), and IL-4 VNTR gene polymorphisms in patients with chronic rhinosinusitis with sinonasal polyposis

Background/aimSinonasal polyposis is a complex chronic disease displaying contributions from multiple genetic and environmental factors. In this study, we analyzed possible genetic factors that increase susceptibility to this widespread inflammatory disease.Materials and methodsA total of 176 adult patients, including 78 patients with sinonasal polyposis and 98 healthy controls, were analyzed for IL-1RN VNTR, IL-2(-330), and IL-4 VNTR gene polymorphisms using polymerase chain reaction and enzyme restriction.ResultsIL-1RN and IL-4 VNTR polymorphisms were notably associated with sinonasal polyposis (P = 0.0001 and P = 0.036, respectively); however, regarding the IL-2(-330) gene polymorphism, no significant difference was shown between the patient and control groups (P = 0.235).ConclusionsOur study indicates that the RN2 allele of IL-1RN and the RP1 allele of IL-4 might be risk factors for developing sinonasal polyposis.

A polymorphism in the IL1B gene (rs16944 T/C) is associated with cutaneous leishmaniasis caused by Leishmania guyanensis and plasma cytokine interleukin receptor antagonist

Nod-like Receptor Protein3 (NLRP3) inflammasome in macrophages infected with Leishmania sp. enhances the secretion of IL-1β. Excess IL-1β production is linked to disease severity in patients with cutaneous leishmaniasis (CL) caused by L. mexicana. Blockade of the NLRP3 inflammasome in cell cultures from skin biopsies of patients with CL caused by L. braziliensis inhibited the release of IL-1β. We hypothesized that common single nucleotide polymorphisms in the IL1B and in its receptor antagonist IL1RN genes may be predictive of CL caused by L. guyanensis. The SNPs –511T/C (rs16944) and +3954C/T (rs1143634) of the IL1B and IL1RN VNTR (rs2234663) were assessed in 881 patients with CL and 837 healthy controls by PCR-RFLP and direct PCR respectively. Plasma cytokines levels were also assayed. The plasma levels of IL-1β were higher in patients compared to control subjects. In contrast, increased plasma levels of IL-1Ra were observed in controls. The rs16944 C/C genotype was more common among the patients (OR = 1.5 [95%CI 1.1–2.0]; P = 0.004) and the C allele suggests susceptibility to CL (OR = 1.2 [95%CI 1.1–1.4]; P = 0.003). The rs16944 C/C genotype shows a tendency to correlate with lower levels of the IL-1Ra cytokine. Low levels of IL-1Ra cytokine and rs16944 C/C genotype seem to confer susceptibility to L. guyanensis-infection in the Amazonas.

Association of interleukin-1 gene polymorphism with risk of gastric and colorectal cancers in an Iranian population.

Chronic inflammation is associated with neoplasms and several types of cancer. Therefore, polymorphisms in the inflammation-related genes could modify the cancer susceptibility. To investigate the associations between IL-1RN VNTR and rs419598 polymorphisms in IL-1 receptor antagonist (IL-1ra) and colorectal cancer (CRC) and gastric cancer (GC) in an Iranian population. In this study, 126 cancer cases (91 CRC and 35 GC) and 97 healthy controls were included. Genotyping of IL-1RN VNTR and rs419598 was performed by PCR amplification and PCR-RFLP, respectively. Logistic regression was applied to identify the independent risk factors for colorectal and gastric cancers by computing the odds ratio (OR) and 95% confidence intervals (95% CI). All statistical analyses were performed using the SPSS statistical software. There were significant differences between cancer groups and control group concerning the frequency of A1/A2 genotypes in IL-1RN VNTR polymorphism. The carrier status of IL-1RN* 2 allele was associated with increased risk of CRC (p = 0.0003; OR = 0.02; 95% CI: 0.491-0.85) and GC (p = 0.0006; OR = 0.106; 95% CI: 0.321-0.035). Also, the homozygous ILRN *2/*2 genotype was associated with increased risk of gastric cancer (p = 0.04; OR = 0.133; 95% CI: 0.020-0.908). There was no association between different alleles of rs419598 and CRC and GC. This study demonstrates an association between the carrier status of IL-1RN* 2 and CRC and GC in an Iranian population.

Genetic influence of cytokine polymorphisms on the clinical outcome of Japanese gastrointestinal cancer patients in palliative care.

Gastrointestinal cancer is one of the most common causes of mortality globally. The present study examined the influence of cytokine genetic polymorphisms [interleukin (IL)-1B C-31T, IL-1RN VNTR, IL-6 C-634G, IL-8 T-251A, IL-10 T-819C and IL-10 A-1082G] on clinical outcomes in patients with gastrointestinal cancer in palliative care. A total of 59 patients with gastrointestinal cancer who were admitted to Iga City General Hospital were analyzed. Genotyping was conducted using a polymerase chain reaction with confronting two-pair primers. Patients with at least one IL-1RN 2 allele demonstrated a significantly better survival (P=0.0275) while those with IL-6-634 G/G demonstrated a worse survival (P=0.0024). Multivariate analyses using the Cox proportional hazard model revealed that those with at least one IL-1RN 2 allele, IL-6-634 G/G or IL-10-1082 A/G had a significantly elevated adjusted hazard ratio of 9.20 (P=0.014), 41.01 (P=0.001) or 6.49 (P=0.046), respectively, compared with those with each homozygous wild-type polymorphism. In addition, the evaluation of weight loss by genotype revealed the potential influence of IL-10 T-819C genotype (P=0.072). IL-1RN, IL-6 and IL-10 polymorphisms were associated with the survival of patients with gastrointestinal cancer, suggesting the clinical feasibility of genetic testing in patients with gastrointestinal cancer in palliative care.

Proinflammatory biomarkers' level and functional genetic polymorphisms in periprosthetic joint infection

ObjectiveThe aims of this study were 1) to identify the level of inflammatory biomarkers interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-17, C-reactive protein (CRP), granulocyte colony-stimulating factor (GCSF), ferritin, and tumor necrosis factor (TNF)-α in serum and synovial fluid samples of patients who underwent revision arthroplasty surgery; 2) to establish the relationship between serum and synovial fluid levels; 3) to determine if any of the 11 genetic polymorphisms of TNFα, IL-1, IL-6, IL-8, IL-17, and GCSF on the encoding genes was associated with periprosthetic joint infection (PJI). MethodsSynovial fluid and serum was collected from 88 patients who underwent revision arthroplasty surgery. The Musculoskeletal Infection Society definition was used to classify these patients into 2 groups: 36 PJIs and 52 aseptic failures. Synovial fluid and serum samples were tested for 9 biomarkers using a micro enzyme-linked immunosorbent assay. Genetic polymorphisms were evaluated with polymerase chain reaction and restriction endonuclease analysis. ResultsSynovial fluid-derived IL-1α, IL-1β, IL-8, IL-17, CRP, GCSF, TNFα, and serum-derived IL-6, IL-17, ferritin, CRP were found suitable to classify PJI and aseptic failure. In addition, IL-17 and CRP levels demonstrated a positive correlation between synovial fluid and serum. TNFα-238, IL6-174, GCSF3R, and IL1 RN-VNTR genetic polymorphisms occurred more frequently in individuals with septic failure. ConclusionSignificant differences between the two groups were observed in the functional polymorphisms of the genes encoding the cytokines investigated. These differences could be interpreted as indicating that there is an association between PJI and genetic polymorphisms. Level of evidenceLevel III, diagnostic study.

High expression of interleukine-1 receptor antagonist in rheumatoid arthritis: Association with IL1RN*2/2 genotype

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and pro-inflammatory cytokines production. IL-1Ra is an anti-inflammatory cytokine codified by IL1RN gene that blocks IL-1 signalling. A VNTR polymorphism of 86 bp in IL1RN gene has been associated with RA risk and regulation of IL-1Ra expression. In this study, we determined mRNA and protein expression of IL-1Ra in RA patients and control subjects (CS). This study included 85 RA patients classified according to the ACR/EULAR 2010 criteria and 67 CS. Polymerase chain reaction was used to identify IL1RN VNTR polymorphism, the expression of sIL-1Ra (secreted isoform) mRNA was determined by SYBR Green-based real time quantitave-PCR assay, and IL-1Ra soluble levels quantification was evaluated by ELISA test. RA patients had higher soluble levels of IL-1Ra than CS (p < .01), sIL-1Ra mRNA expression was higher in RA patients compared to CS (p < .01). Carriers of IL1RN*2/2 homozygous genotype show increased IL-1Ra soluble levels compared to IL1RN*long/long and IL1RN*2/long genotypes (p < .05) in the CS group, whereas mRNA expression in carriers of IL1RN*2/2 genotype was 1.2 times higher compared to IL1RN*long/long genotypes in the same group. Regarding RA patients, high expression of sIL-1Ra mRNA on carriers of IL1RN*long/long genotype was observed. Nevertheless, in RA patients IL-1Ra soluble levels among genotypes did not show significant differences. High expression of IL-1Ra in RA patients under treatment or not with antirheumatic drugs was detected. Additionally, carriers of IL1RN*2/2 genotype had higher IL-1Ra expression than carriers of other genotypes.

Candidate gene analysis in pathogenesis of surgically and non-surgically treated necrotizing enterocolitis in preterm infants

Necrotizing enterocolitis (NEC) is one of the most severe and unpredictable complications of prematurity. There are two possible mechanisms involved in the pathogenesis of NEC: individual inflammatory response and impaired blood flow in mesenteric vessels with secondary ischemia of the intestine. The aim of this study was to evaluate the possible relationship between polymorphisms: Il-1β 3953C>T, Il-6 −174G>C and −596G>A, TNFα −308G>A, and 86 bp variable number tandem repeat polymorphism of interleukin-1 receptor antagonist (Il-1RN VNTR 86 bp) and three polymorphisms that may participate in arteries tension regulation and in consequence in intestine blood flow impairment: eNOS (894G>T and −786T>C) and END-1 (5665G>T) and NEC in 100 infants born from singleton pregnancy, before 32 + 0 weeks of gestation, exposed to antenatal steroids therapy, and without congenital abnormalities. In study population, 22 (22%) newborns developed NEC. Surgery-requiring NEC was present in 7 children. Statistical analysis showed 20-fold higher prevalence of NEC in infants with the genotype TT [OR 20 (3.71–208.7); p = 0.0004] of eNOS 894G>T gene polymorphism. There was a higher prevalence of allele C carriers of eNOS 786T>C in patients with surgery-requiring NEC [OR 4.881 (1.33–21.99); p = 0.013]. Our investigation did not confirm any significant prevalence for NEC development in another studied genotypes/alleles. This study confirms the significant role of polymorphisms that play role in intestine blood flow. Identifying gene variants that increase the risk for NEC development may be useful in screening infants with inherent vulnerability and creating strategies for individualized care.

Common variants in IL-1RN, IL-1β and TNF-α and the risk of ovarian cancer: a case control study.

Aim of the studySeveral studies implicated altered inflammatory response in the susceptibility to ovarian cancer, and polymorphisms in inflammatory cytokines were shown to play an important role in the development of malignancies, including ovarian cancer (OC). Here we investigated the relationship between polymorphisms in IL-1β (-511C>T), IL-1RN VNTR, TNF-α (-308G>A), and TNF RII (-322 VNTR) and OC risk in Tunisian women.Methods and resultsStudy subjects comprised 62 OC patients and 126 healthy women. Genotyping was done from genomic DNA obtained from blood simple by PCR. Positive association between IL-1RN (-VNTR) A1 allele (p = 0.0069; OR = 2.04; 95% CI:1.17-3.58) and OC risk, while negative association was seen with the A3 allele (P = 0.0034; OR = 0.09; 95% CI: 0.00-0.64), suggesting a protective role by the A3 allele. For IL-1β (-511C>T), homozygous C/C genotype was associated with significantly increased risk of OC (p = 0.0002; OR = 4.14; 95% CI: 1.77-9.76), while heterozygote C/T genotype was linked with reduced risk of OC (p = 0.0033; OR = 0.40; 95% CI: 0.20-0.78). Furthermore, TNF-α -308A allele was significantly associated with heightened risk of OC (p = 0.016; OR = 1.70; 95% CI: 1.08-2.69), and homozygote G/G genotype was associated with decreased risk of OC (p = 0.0018; OR = 0.25; 95% CI: 0.09-0.66). In contrast, TNFRII (-322 VNTR) polymorphism was not associated with altered OC risk in the studied group.ConclusionsThe significant association between IL-1RN VNTR, IL1-β (-511), TNF-α (-308) and OC susceptibility in Tunisian women confirms a role for altered inflammatory response in ovarian cancer pathogenesis.

Association of genetic polymorphisms of IL1β -511 C>T, IL1RN VNTR 86bp, IL6 -174 G>C, IL10 -819 C>T and TNFα -308 G>A, involved in symptomatic patients with dengue in Brazil.

In this study, single nucleotide polymorphisms (SNP) of interleukin (IL) 1β -511C>T, IL1RN VNTR 86bp, IL6 -174G>C, IL10 -819C>T and TNFα -308G>A were analyzed by PCR-RFLP with symptoms of dengue with the clinical features. 196 individuals admitted to the São José Infectious Diseases Hospital with suspected dengue infection. Dengue was confirmed in 111 of the patients. The control group consisted of 85 other individuals confirmed without dengue. It was demonstrated that the presence the T allele of IL1β (P<0.05) was associated with susceptibility to developing the disease. Other results also suggested that the polymorphism in the combinations IL6×IL1β (C and T alleles, respectively), IL1β (T allele)×IL1RN (*2/*2 genotype), IL6 (C allele)×TNFα (A allele), IL10 (C/T genotype)×TNFα (A/A genotype) (P<0.01, P=0.01, P<0.05 and P=0.03, respectively) were associated with predisposition to developing the disease and its symptoms. In summary, the findings of this study in a Brazilian population point out the importance of studies of combinations of polymorphisms in the development of dengue, which can increase the risk of dengue infection and its severity.

VNTR polymorphisms of the IL-4 and IL-1RN genes and their relationship with frailty syndrome in Mexican community-dwelling elderly.

Inflammation is a key event that is closely associated with the pathophysiology of frailty. The relationship of genetic polymorphisms into inflammatory cytokines with frailty remains poorly understood. The aim of this study was to investigate the association between VNTR polymorphisms of the IL-4 and IL-1RN genes with the risk of frailty. We included a sample of 630 community-dwelling elderly aged 70 and older. Both IL-4 and IL-1RN VNTR polymorphisms were genotyped by the polymerase chain reaction (PCR) method. Mean age was 77.7years (SD=6.0) and 52.5% were women. The participants classified as frail were more likely to be older, had lower MMSE score (p<0.001), and had more disability for IADL (p<0.001) and ADL (p<0.001). Genotypic and allelic frequencies for the IL-4 VNTR polymorphism did not show significant differences between study groups (p>0.05). However, we just observed a significant difference in the allelic frequencies for the A2 allele of the IL-1RN VNTR polymorphism between frail and nonfrail groups (OR 1.84, 95% CI 1.08-3.12, p=0.02). In addition, we analyzed the combined effect of the IL-4 and IL-1RN VNTR polymorphisms and their possible association with frailty, where the combined IL-4 (low) -IL-1Ra (high) genotype was identified as a marker of risk to frailty syndrome (OR 7.86, 95% CI 1.83-33.69, p=0.006). Our results suggest that both A2 allele and the combined IL-4 (low) -IL-1Ra (high) genotype might be genetic markers of susceptibility to frailty in Mexican elderly.

Variations in inflammatory genes as molecular markers for prediction of inflammatory bowel disease occurrence.

Research on inflammatory bowel disease (IBD) has highlighted genes involved in the regulation of inflammatory responses as contributors to disease pathogenesis. This study aimed to evaluate the associations between IBD and variations in NOD2, TLR4, TNF-α, IL-6, IL-1β and IL-1RN genes, and to use the genetic data obtained in predictive modeling. A total of 167 IBD patients and 101 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Using the genotype data attained as the input to various classification algorithms, IBD prediction models were designed. The area under the receiver operating characteristic curve (AUROC) was used to measure their performance. Significant associations were found between Crohn's disease (CD) and minor NOD2 variants, as well as TLR4 299Gly, TNF-α G-308A, IL-6 G-174C and IL-1RN VNTR A2 variants, while ulcerative colitis (UC) was associated only with IL-1RN VNTR A2 variants. CD and UC showed highly significant difference in the allelic distribution of TNF-α G-308A, where the A allele was found to be related to CD, and the G allele to UC. A combined effect of patients' gender and TLR4 variants was observed among CD patients. When all analyzed genotype and gender data were used, prediction performance achieved a maximum AUROC of 0.690 for CD and 0.601 for UC dataset. Variations in the genes involved in immune regulation are genetic factors of importance in IBD susceptibility that could potentially be used as predictors of disease development.

Lack of Association Between the IL1B (-511 and +3954), IL1RN VNTR Polymorphisms and Tuberculosis Risk: A Meta-analysis.

Several recent studies have provided evidence that polymorphisms in the interleukin-1 (IL1) gene are implicated in tuberculosis (TB). However, results of different studies are inconsistent. The aim of this study was to perform a meta-analysis investigating the association of the IL1B (-511 and +3954) and IL1RN VNTR polymorphisms with TB risk. A systematic review of the English literature was conducted by searching Pubmed, Scopus, and ISI Web of Knowledge databases for relevant studies. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using fixed effects models. Between-study heterogeneity and publication bias were also evaluated. Nine case-control studies including 3327 participants were reviewed and analyzed. Our results did not indicate any association of the IL1B (-511 and +3954) and IL1RN VNTR polymorphisms with TB risk in the overall populations. The pooled OR of the IL1B -511 polymorphism was 1.09 (95% CI 0.87-1.36) for the dominant model, 1.11 (0.89-1.38) for the recessive model, 1.15 (0.87-1.50) for the homozygote model, and 1.07 (0.94-1.23) for the allelic comparison model. ORs for the IL1B +3954 and IL1RN VNTR polymorphisms were similar. In subgroup analysis stratified by ethnicity, the results revealed no association between these polymorphisms and TB risk in black people, Asians, and Caucasians, respectively. We did not identify significant between-study heterogeneity across all studies, and there was no evidence of publication bias. Our results indicate there is a lack of association between the IL1B (-511 and +3954), IL1RN VNTR polymorphisms and TB risk.

Interleukin-1β, Interleukin1-Ra, Interleukin-10, and tumor necrosis factor-α polymorphisms in Tunisian patients with rheumatoid arthritis

ObjectivesThe aim of this study was to investigate the role of IL-1β (−511C>T), TNFα (-308 G>A), IL-10 (-1082 G>A) and IL-1RN VNTR polymorphisms in the susceptibility to rheumatoid arthritis (RA) in Tunisians. Patients and methodsUsing PCR-based methods, 104 RA patients and 150 healthy controls were investigated. We compared allele and genotype frequencies in RA patients versus controls and analyzed their correlations with erosive form (EF). ResultsIL1-RN VNTR A1A3 genotype is associated with higher risk of RA (P=0.012, OR=4.31). Among the cases, males who carry this genotype were more exposed to RA (P=0.044, OR=8, 47). For IL1- β gene, a significantly higher frequency of the -511C/C genotype was observed in RA patients in comparison to controls (P=0.013, OR=2.45). This higher frequency was especially observed in women (P=0,003, OR=3.42). In contrast, IL10−1082G/G genotype was less common in patients (P=0.046, OR=0.46). According to EF, men carrying IL1-RN VNTR A1A3 (P=0.005 OR=5.28) and IL1-β−511C/C (P=0.015 OR=2.61) genotypes develop non EF of RA. Moreover, TNFα-308 A allele (P=0.024, OR=1.84) and A/A genotype (P=0.033, OR=3.1) were positively associated to EF of RA. However, G allele (P=0.024, OR=0.31) and GG genotype (P=0.31, OR=0.031) of the TNFα-308 were protectors. ConclusionOur results indicated that IL-1RN VNTR, IL-1β (−511C>T) and IL-10 (-1082 G>A) are associated with susceptibility to RA, and that IL-1RN VNTR, IL-1β (−511C>T) and TNFα (-308 G>A) are associated with severity of RA.