IL-18 Variants Research Articles

IL-18 signaling is regulated by caspase 6/8 and IL-18BP in turbot (Scophthalmus maximus)

Interleukin (IL)-18 is synthesized as a precursor that requires intracellular processing to become functionally active. In human, IL-18 is processed by caspase 1 (CASP1). In teleost, the maturation and signal transduction mechanisms of IL-18 are unknown. We identified two IL-18 variants, IL-18a and IL-18b, in turbot. IL-18a, but not IL-18b, was processed by CASP6/8 cleavage. Mature IL-18a bound specifically to IL-18 receptor (IL-18R) α-expressing cells and induced IL-18Rα—IL-18Rβ association. Bacterial infection promoted IL-18a maturation in a manner that required CASP6 activation and correlated with gasdermin E activation. The mature IL-18a induced proinflammatory cytokine expression and enhanced bacterial clearance. IL-18a-mediated immune response was suppressed by IL-18 binding protein (IL-18BP), which functioned as a decoy receptor for IL-18a. IL-18BP also functioned as a pathogen pattern recognition receptor and directly inhibited pathogen infection. Our findings revealed unique mechanism of IL-18 maturation and conserved mechanism of IL-18 signaling and regulation in turbot, and provided new insights into the regulation and function of IL-18 related immune signaling.

IL18 rs360717 and rs187238 genetic variants are associated with migraine diagnosis.

Migraine is a genetically determined disorder that predisposes to recurrent episodes of headache. Interleukin (IL)-18 is a pro-inflammatory cytokine that seems to play a role in migraine pathophysiology, and its genetic variants could potentially impact susceptibility to migraine. To investigate the association between IL18 rs360717 and rs187238 genetic variants with migraine diagnosis and its clinical characteristics. A case-control study was conducted with 152 people with migraine and 155 healthy controls, matched by sex, age, ethnicity, and body mass index. Clinical characteristics of migraine, as well as validated questionnaires regarding disability and impact of migraine, presence of allodynia, anxiety, depression, and hyperacusis were collected. Genotyping for IL18 rs360717 and rs187238 variants was performed using real-time polymerase chain reaction (qPCR) and TaqMan™ method. The IL18 rs360717A and rs187238G alleles were associated with increased chance of being diagnosed with migraine (OR = 1.53, 95%CI 1.05-2.24, p = 0.028 and OR = 1.46, 95%CI 1.00-2.14, p = 0.049, respectively). In the dominant model, the rs360717GA + AA genotypes were also associated with a higher chance of migraine than the GG genotype (OR = 1.69, 95%CI 1.05-2.73, p = 0.030). In women, in addition to the previous associations, there was also an effect of the variants on the chance of migraine in the codominant models and dominant models. Furthermore, among women, there was an influence on the prevalence of postdrome perception with rs360717GA + AA (OR = 3.04, 95%CI 1.10-8.42, p = 0.032) and rs187238CG + GG (OR = 2.97, 95%CI 1.08-8.21, p = 0.035). IL18 rs360717 and rs187238 variants were associated with migraine diagnosis and postdrome symptoms, especially in women. This study has demonstrated that IL18 rs360717 and rs187238 variants play a role in migraine, influencing the chance of being diagnosed with migraine, particularly among women. There are prospects that IL18 variants could be considered potential genetic biomarkers for migraine.

Abstract 4076: Interleukin-18 engineered for resistance to IL-18 binding protein (IL-18BP) and half-life extension to enhance its therapeutic potential

Abstract Interleukin-18 (IL-18) possesses a unique combination of innate and acquired immune functions with high potential to be transformative in cancer immunotherapy of solid tumors. In clinical studies, recombinant wild-type IL-18 was limited by rapid upregulation of IL-18 binding protein (IL-18BP), which serves as a negative feedback checkpoint of the IL-18 pathway. As its name implies, IL-18BP tightly binds to IL-18, thereby blocking its ability to activate the IL-18 receptor. We have focused our protein engineering efforts to obtain variants of IL-18 that are resistant to IL-18BP suppression while retaining IL-18 biological activity. To further capitalize on the immunological effects of IL-18, the IL-18BP resistant variants were fused to half-life extension protein scaffolds for enhanced in vivo exposure. Rational protein design and combinatorial approaches were used to generate a pool of IL-18 variants that were screened for potency and resistance to IL-18BP. Several IL-18 variants showed undetectable binding to IL-18BP (up to 1 mM IL-18BP) and displayed a spectrum of potencies relative to recombinant wild-type IL-18. Importantly, these variants retained their full biological activity in the presence of super-physiological levels of IL-18BP, as tested with in vitro cell-based IFN-γ release assays. In vivo pharmacokinetic studies in mice compared several IL-18BP resistant variants fused to a half-life extension scaffold with a non-half-life enhanced IL-18BP resistant variant. The half-lives for the fusion proteins ranged from 15 - 30h, while the non-fused variant showed a half-live of 0.6h. Furthermore, the IL-18 variants displayed a more durable, Th1 immune response compared to a non-half-life enhanced variant. Thus, IL-18 variants with strong resistance to IL-18BP that are fused to a half-life extension protein scaffold displayed enhanced pharmacokinetic and pharmacodynamic properties in preclinical mouse models. These protein engineering modifications will enable us to select an appropriate development candidate with enhanced pharmaceutical properties to achieve the full therapeutic potential of IL-18 to assess in patients with cancer. Citation Format: Jean Chamoun, Clifford DiLea, Kristiana Dreaden, Pinar Gurel, Joshua Heiber, Robert G. Newman, Su-Ping Pearson, Chunhua Wang, Yanchun Zhao, Mark Whitmore. Interleukin-18 engineered for resistance to IL-18 binding protein (IL-18BP) and half-life extension to enhance its therapeutic potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4076.

IL-18 and CD14 variants in chronic HBV predisposition: a case-control study with in silico analyses focused on transcription and splicing

Hepatitis B virus (HBV), a vaccine-avoidable infection, is a health concern worldwide, leading to liver disorders such as acute self-constraint and chronic hepatitis, liver failure, hepatic cirrhosis, and even hepatocellular carcinoma if untreated. ‘Immunogeneticprofiling’, genetic variations of the pro- and anti-inflammatory cytokines responsible for regulating the immune responses, cause person-to-person differences and impact the clinical manifestation of the disease. The current experimental–bioinformatics research was conducted to examine whether promoteric IL-18–rs187238 C > G and –rs1946518 T > G and intronic CD14–rs2569190 A > G variations are associated with chronic HBV. A total of 400 individuals (200 in each case and control group) participated in the study and were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The data was also assessed bioinformatics-wise for conservation, genomic transcription and splicing, and protein interactions. Findings proposed that unlike the IL-18–rs1946518 T > G and CD14–rs2569190 A > G, the IL-18–rs187238 C > G is a protector against chronic HBV (odds ratio [OR] = 0.62, 95% confidence intervals [CI]: 0.46–0.83, and p = 0.002). The TG/CC/AA, TG/CC/AG, TT/CC/AG, and GG/CC/AA combined genotypes significantly increased chronic HBV risk (p < 0.05), while the IL-18 G/T and G/G haplotypes lessened it (p < 0.05). Moreover, IL-18–rs1946518 T > G is in the protected genomic regions across mammalian species. In contrast to the IL-18–rs1946518 T > G, IL-18–rs187238 C > G is likely to create novel binding sites for transcription factors, and the CD14–rs2569190 A > G presumably changed the ribonucleic acid splicing pattern. More research on larger populations and other ethnicities is required to authenticate these results.

Genetic variants IL18 -105G&gt;A and -137G&gt;C associated with susceptibility to migraine

IntroductionFew studies have been conducted into neurogenic inflammation and neuroinflammation in respect of migraine. However, evidence suggests that the immune system may exert an influence over trigeminal activation and cortical spreading depression in individuals suffering from migraine. The interleukin (IL)-18 is a pro-inflammatory cytokine and increased plasma levels have been confirmed in individuals with migraine. However, as yet, the genetic variants of IL-18 have not been investigated in the context of migraine. ObjectiveTo investigate the association between genetic variants IL18 -105G&gt;A (rs360717) and IL18 -137G&gt;C (rs187238) and susceptibility to migraine and its clinical characteristics. Subjects and MethodsCase control study comprising 307 participants, of whom 152 had a diagnosis of migraine and 155 were healthy controls, paired by sex, age, ethnicity and BMI. The clinical and demographic data were evaluated. The patients with migraine were interviewed using a structured form containing information about the type of migraine (with or without aura, episodic or chronic), age at onset of the disease, frequency of attacks, accompanying symptoms that triggered headaches. The patients also answered validated questionnaires to evaluate incapacity (Migraine Disability Assessment - MIDAS) and impact (Headache Impact Test - HIT-6) for migraine, the presence of allodynia (ASC-12), as well as symptoms of anxiety (State Anxiety Inventory - STAI 1 and 2), depression (Beck Depression Inventory) and a hyperacusis scale.The genetic variants IL18 -105G&gt;A (rs360717) and IL18 -137G&gt;C (rs187238) were identified using polymerase chain reaction (PCR) and the fluorescence levels of PCR products were evaluated using a Step One thermocycler (Applied Biosystems). The analyses were conducted using the dominant, codominant, recessive and overdominant genetic models. (To see the complete abstract, please, check out the PDF).

Immunopathogenesis and Immunogenetic Variants in COVID-19.

Coronavirus disease 2019 (COVID-19) continues to spread globally despite the discovery of vaccines. Many people die due to COVID-19 as a result of catastrophic consequences, such as acute respiratory distress syndrome, pulmonary embolism, and disseminated intravascular coagulation caused by a cytokine storm. Immunopathology and immunogenetic research may assist in diagnosing, predicting, and treating severe COVID-19 and the cytokine storm associated with COVID-19. This paper reviews the immunopathogenesis and immunogenetic variants that play a role in COVID-19. Although various immune-related genetic variants have been investigated in relation to severe COVID-19, the NOD-like receptor protein 3 (NLRP3) and interleukin 18 (IL-18) have not been assessed for their potential significance in the clinical outcome. Here, we a) summarize the current understanding of the immunogenetic etiology and pathophysiology of COVID-19 and the associated cytokine storm; and b) construct and analyze protein-protein interaction (PPI) networks (using enrichment and annotation analysis) based on the NLRP3 and IL18 variants and all genes, which were established in severe COVID-19. Our PPI network and enrichment analyses predict a) useful drug targets to prevent the onset of severe COVID-19, including key antiviral pathways such as Toll-Like-Receptor cascades, NOD-like receptor signaling, RIG-induction of interferon (IFN) α/β, and interleukin (IL)-1, IL-6, IL-12, IL-18, and tumor necrosis factor signaling; and b) SARS-CoV-2 innate immune evasion and the participation of MYD88 and MAVS in the pathophysiology of severe COVID-19. The PPI network genetic variants may be used to predict more severe COVID-19 outcomes, thereby opening the door for targeted preventive treatments.

Characterization of the turbot (Scophthalmus maximus) interleukin-18: Identification of splicing variants, phylogeny, synteny and expression analysis

Interleukin-18 (IL-18) is a pro-inflammatory cytokine that belongs to the interleukin-1 (IL-1) family of cytokines. As occurs with IL-1β, it is synthetized as an inactive precursor peptide that is mainly processed by the cysteine protease caspase-1 in the inflammasome complex. In mammals, and in collaboration with IL-12, it has been described as an important cytokine controlling the Th1-mediated immune responses through the induction of IFN-γ. Although its function in mammals is well stablished, the activity of this cytokine in teleost remains to be elucidated. This could be due, among other things, to the absence of this gene in the fish model species zebrafish, but also to its complex regulation. As it was observed for rainbow trout and human, il18 splicing variants were also found in turbot, which could represent a regulatory mechanism of its bioactivity. In the case of turbot, three splicing variants were observed (SV1-3), and one of them showed an insertion of 10 amino acids in the middle of the potential caspase-1 cleavage position, reflecting that this is probably a form resistant to the processing by the inflammasome. Phylogenetic and three-dimensional analyses of turbot Il18 revealed that it is relatively well-conserved in vertebrates, although only a partial conservation of the gene synteny was observed between fish and mammals. As it was expected, turbot il18 splicing variants were mainly expressed in immune tissues under healthy conditions, and their expression was induced by a bacterial challenge, although certain inhibitions were observed after viral and parasitic infections. In the case of the viral challenge, il18 downregulations did not seem to be due to the effect of type I IFNs.

Role of combinations of polymorphisms of cytokine genes in the diagnosis of Legg–Calve–Perthes disease in children

Background. LeggCalvePerthes disease (LCPD) is an idiopathic avascular femoral head osteonecrosis. The early disease stage is associated with the development of synovitis of the hip joint linked to the overproduction of factors induced by hypoxia as well as of interleukin (IL)-6. Associations of individual polymorphic variants of cytokine genes with LCPD have been shown. Moreover, alterations in the cytokine regulatory cascade are considered an important link in the pathogenesis of synovial inflammation in the early stages of LCPD. Accordingly, this process may be associated with a certain combination of polymorphic variants of the genes for pro-inflammatory and anti-inflammatory cytokines.&#x0D; Aim. This study aimed to study the associations of polymorphic variants of the genes for pro-inflammatory and anti-inflammatory IL with LCPD.&#x0D; Materials and methods. In this casecontrol study, the main and control groups were composed of 26 children with LCPD and 40 healthy children (all aged 311 years), respectively. Genotyping of IL10 (rs1800896), IL13 (rs20541), IL18 (rs187238), IL18 (rs5744292), IL1a (rs1800587), IL1RA (POL_GF_58), IL-1Ra (rs4251961), IL1B (rs16944), IL1B (rs1143634), IL4 (POL_GF_59), IL4 (rs2243250), IL6 (rs1800796), IL6 (rs1800795), INF (rs2430561), TGF (rs1800469), and TNF (rs1800629) was performed by polymerase chain reaction (PCR) using TaqMan probes to the corresponding polymorphic variants of genes produced by Thermo Fisher Scientific (USA) on an amplifier ViiATM 7 RealTime PCR System (Life Technologies, USA). Statistical processing of the results was carried out using the SNPstats program and multifactor dimensionality reduction.&#x0D; Results. The study revealed three separate LCPD-potentiating genotypes of polymorphic variants of cytokine genes: IL10 (rs1800896; TC)*T/C (OR 6.50), IL4 (POL_GF_49, VNTR, Intron4)*2R/2R (OR 12.32), and IL-6 (rs1800796; GC)*G/C (OR 4.08). Two polymorphic variants of the IL4 gene (POL_GF_49, VNTR, Intron4, and rs2243250; CT) had a pronounced synergism with respect to the diagnosis of LCPD. Moderate synergy with respect to the diagnosis of LCPD demonstrated the intergenic interaction of IL6 (rs1800796, GC) with tumor necrosis factor- (rs1800629, GA). Moderate antagonism between LCPD and intergenic interactions was obtained for polymorphic variants of IL18 (rs5744292, TC) and transforming growth factor- (rs1800469, AG) genes.&#x0D; Conclusions. The pathogenesis of synovitis and subsequent osteonecrosis in LCPD is associated with a combination of polymorphic variants of the genes of pro-inflammatory and anti-inflammatory cytokines, as well as of DNA variants of the pro-allergic IL4 gene.

IL-18 Serum Levels and Variants of the Serotonin Transporter Gene Are Related to Awareness of Emotions in Healthy Subjects: A Preliminary Study

Objective: Interaction between the nervous and immune systems may influence emotions, ultimately affecting human health. Cytokines may play a role in developing emotional dysregulation as in alexithymia, a personality construct characterized by the subclinical inability to identify and describe emotions, often associated with several psychiatric and psychosomatic disorders. The proinflammatory cytokine IL-18, with a recognized role in brain functions, may influence serotonin metabolism and appears to be associated with alexithymia. Healthy individuals carrying the long allele (L) of the serotonin transporter gene polymorphic region (5-HTTLPR), and thus having lower concentrations of serotonin in the synaptic cleft, show a greater tendency toward alexithymia, with some gender differences. To explore a potential physiological interaction between IL-18, serotonin neurotransmission, and alexithymia, we investigated whether IL-18 serum levels and 5-HTTLPR are linked to alexithymic traits in healthy subjects. Methods: We measured IL-18 serum levels in 115 Italian-Caucasian healthy subjects genotyped for 5-HTTLPR allele variants, divided by gender and assessed for alexithymia scores using the 20-item Toronto Alexithymia Scale. Results: IL-18 levels are significantly more elevated in individuals with the LL genotype (n = 25) than in carriers of the short allele (n = 90, p = 0.0073). Specifically, in LL males (n = 11), i.e., the group with the most relevant increase in IL-18, cytokine values positively correlated with difficulty identifying feelings, which is a component of alexithymia (r = 0.634, p = 0.036). Conclusions: These results indicate a possible novel interaction between IL-18 and the serotoninergic system to mediate emotional unawareness, suggesting putative biological predictors of emotional dysregulation, which in turn can act as a risk factor for a variety of medical conditions in susceptible subjects.

Significant association of the cytokine variants with head and neck cancer risk: evidence from meta-analysis.

To evaluate the possible relevance of the IL-18-137 G>C (rs187238), IL-18-607 C>A (rs1946518) and IL-4-590 C>T (rs2243250) polymorphisms to the genetic susceptibility of head and neck cancer. Data were retrieved from PubMed, EMBASE, Web of Science and CNKI databases, and the results were independently analysed by two reviewers using Stata 14.0 software. After searching for and assessing the literature, a total of thirteen studies involving 2,959 patients newly diagnosed as head and neck cancer and 3,622 controls from healthy donors were analysed. The results suggested that a strong relationship between patients and healthy controls was observed in the IL-18-137 G>C polymorphism in consistence with the result (CC vs. GG + GC: OR = 1.63, P = 0.004; CC vs. GG: OR = 1.82, P = 0.001). When stratified by cancer type, ethnicity and the source of control samples, significant and elevated risks were obtained in the genetic susceptibility to Asian patients with NPC in all genetic models and in those studies using the PCR-RFLP test method. In addition, comparable results were obtained for the IL-18-607 C>A polymorphism, especially for Asian patients with NPC. It should be a potential association between IL-18 variants and nasopharyngeal carcinoma. Furthermore, IL-18 gene variants might be considered as a critical role in predicting the occurrence of nasopharyngeal carcinoma in Asian population. However, the IL-4-590 C>T polymorphism does not influence the development of head and neck cancer.

Multiple genetic variants associated with posttransplantation diabetes mellitus in Chinese Han populations.

Posttransplantation diabetes mellitus (PTDM) is a major complication after solid organ transplantation. This study is to investigate the association of nine genetic variant factors and PTDM in Chinese Han patients. HLA-DP (rs3077, rs9277535), HLA-DQ (rs7453920), signal transducer and activator of transcription 4 (STAT4) (rs7574865), IL-28B (rs12979860, rs8099917, and rs12980275), and IL-18 (rs1946518 and rs187238) were investigated in 260 liver transplant recipients (PTDM vs non-PTDM) by high-resolution melting curve analysis. Serum interleukin (IL)-1β, IL-6, IL-8, IL-17, interferon-γ, inducible protein-10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1b were analyzed by a Bio-Plex suspension array system (Bio-Plex Multiplex Immunoassays, Bio-Rad, Hercules, CA, USA). Signal transducer and activator of transcription 4 (rs7574865) T allele and IL-18 (rs1946518) A allele increase the risk for insulin resistance and PTDM. Recipients with STAT4 (rs7574865) T allele are associated with an increased concentration of IL-1β, interferon-γ, monocyte chemoattractant protein, and macrophage inflammatory protein-1b. The genetic variants of STAT4 (rs7574865) and IL-18 (rs1946518) may be new important markers for PTDM.

Retraction Note to: IL-18 genetic polymorphisms may contribute to the pathogenesis of tuberculosis among Asians: a meta-analysis of case-control studies.

This current meta-analysis of case–control studies was continued to investigate whether the genetic polymorphisms of IL-18 gene contribute to the occurrence and progression of tuberculosis (TB). We searched certain English and Chinese databases for relevant studies without language restrictions. Meta-analysis for the moment was performed with the adoption of the STATA statistical software. Crude OR and its corresponding 95 % confidence interval (95 % CI) were calculated as estimates of relative risk for UC under different genetic models. Seven case–control studies (TB patients = 1,325, healthy subjects = 1,778) were included for the following analysis. We evaluated two functional polymorphisms (rs1946518 C>A and rs187238 G>C). Pooled OR within the progression of statistical analysis indicated that the specific polymorphism of IL-18 rs1946518 C>A showed a closely relationship with the elevated susceptibility to TB under those three genetic models (allele model: OR 1.24, 95 % CI 1.11–1.38, P < 0.001; dominant model: OR 1.41, 95 % CI 1.21–1.65, P < 0.001; homozygous model: OR 1.46, 95 % CI 1.15–1.86, P = 0.002; respectively). However, we observed no statistical associations of the IL-18 rs187238 G>C polymorphism with the susceptibility to TB under any of the genetic models (all P > 0.05). Country-stratified analysis results detected that the variants of IL-18 may be strongly enrolled in the risk of TB among populations in China (allele model: OR 1.19, 95 % CI 1.06–1.33, P = 0.003; recessive model: OR 1.54, 95 % CI 1.00–2.36, P = 0.048; homozygous model: OR 1.59, 95 % CI 1.09–2.33, P = 0.016; respectively), but not among populations in Iran, Korea and India (all P > 0.05). Current results provide strong evidence that IL-18 mutations may be evidently related to the occurrence and development of TB, especially for the rs1946518 C>A polymorphism among populations in China.

Functional genetic variability at promoters of pro-(IL-18) and anti-(IL-10) inflammatory affects their mRNA expression and survival in prostate carcinoma patients: Five year follow-up study.

Inflammation is an important hallmark of all cancers. The net inflammatory response is determined by a delicate balance between pro- and anti-inflammatory cytokines, which, in turn, is determined by the genetic make-up. The present study investigates the role of variations in the promoter regions of IL-18 and IL-10 (anti-inflammatory) cytokines on mRNA expressions and survival in prostate cancer (PCa) patients. The study was conducted on 584 volunteer males (291 patients of PCa, between 40-80 years of age. Genetic variants were studied by using RFLP and confirmed by probe based method. Expressions of mRNA were evaluated by real-time PCR (Roche light cycler 480). Relative mRNA and fold change gene expressions were analyzed by ([1/2] (ΔCt) ) and (2(-ΔΔCt) ) methods, respectively, and 5 year follow-ups were evaluated by Log-rank (Mantel-Cox) test with Log-rank test for trends. IL-18 mRNA expression was significantly elevated in GG genotypes (at -137) of PCa with relative mRNA expression of 13.95, that is, 8.48 folds higher (P < 0.05) than controls; and showed a significant median survival of 1243 days. The CC genotypes of IL-10 at both loci (-819 T/C and -592C/A) showed 3.63 and 3.52 higher relative mRNA expressions than controls, but poor survival of 984 and 1052 days than TT of 1359 days and AA of 1371 days. Genetic variants of pro-inflammatory IL-18 which showed higher relative mRNA expressions have better survival. Genetic variants of anti-inflammatory IL-10 with higher relative mRNA expression showed decreased chances of survival.

Genetic variability at promoters of IL-18 (pro-) and IL-10 (anti-) inflammatory gene affects susceptibility and their circulating serum levels: An explorative study of prostate cancer patients in North Indian populations

Inflammation is an important hallmark of all types of cancers with a well-established role in carcinogenesis. The net inflammatory response is determined by the balance between pro- and anti-inflammatory cytokines, the levels of which may be affected by the genetic make-up.Interleukin (IL)-18, a pro-inflammatory cytokine expressed by various cells including those of the prostate, is a key mediator of anti-cancer immune response. IL-10, an anti-inflammatory cytokine associated with tumour malignancy, causes escape from immune surveillance. This study hypothesizes that genetic variants of IL-18 (−607 C/A and −137 G/T) and IL-10 (−819 C/T and −592 C/A) may influence the circulating levels of these interleukins, thereby generating susceptibility risk to prostate cancer.The study was conducted on 676 subjects (controls and patients of prostate cancer (PCa): 291 each; and 94 patients with benign prostate hypertrophy (BPH)). Genotyping was performed by PCR-RFLP and Real-Time PCR probe-based method. Circulating interleukin levels were obtained by ELISA.Circulating IL-18 levels were significantly elevated in cancer and BPH patients carrying GG genotypes for −137 of IL-18. The trend of circulating IL-18 levels was GG>GC>CC, observed in all groups. The −137 genetic variants of IL-18 significantly associated with PCa risk were GC, CC, and GC+CC, compared to GG (OR: 1.71, 95% CI: 1.20–2.46; OR: 3.35, 95% CI: 2.03–5.53; and OR: 2.05, 95% CI: 1.46–2.87, respectively). A significant association of AA and CA+AA against CC genotype was observed at −607 locus of IL-18 (OR: 0.46, 95%CI: 0.29–0.72; OR: 0.61, 95% CI: 0.41–0.90, respectively).Significantly elevated levels of IL-10 were observed with TT (wild) genotype at −819 of IL-10, compared to the CC (homozygous mutant) genotype in all three groups of subjects. However, no significant association was found between IL-10 promoter genotypes and PCa risk.We conclude that genetic variants of IL-18 and IL-10 promoters influence the circulating levels of these interleukins. Variations at −137 and −607 loci of IL-18 are associated with susceptibility to PCa.

IL-18 genetic polymorphisms may contribute to the pathogenesis of tuberculosis among Asians: a meta-analysis of case-control studies.

This current meta-analysis of case-control studies was continued to investigate whether the genetic polymorphisms of IL-18 gene contribute to the occurrence and progression of tuberculosis (TB). We searched certain English and Chinese databases for relevant studies without language restrictions. Meta-analysis for the moment was performed with the adoption of the STATA statistical software. Crude OR and its corresponding 95 % confidence interval (95 % CI) were calculated as estimates of relative risk for UC under different genetic models. Seven case-control studies (TB patients = 1,325, healthy subjects = 1,778) were included for the following analysis. We evaluated two functional polymorphisms (rs1946518 C>A and rs187238 G>C). Pooled OR within the progression of statistical analysis indicated that the specific polymorphism of IL-18 rs1946518 C>A showed a closely relationship with the elevated susceptibility to TB under those three genetic models (allele model: OR 1.24, 95 % CI 1.11-1.38, P < 0.001; dominant model: OR 1.41, 95 % CI 1.21-1.65, P < 0.001; homozygous model: OR 1.46, 95 % CI 1.15-1.86, P = 0.002; respectively). However, we observed no statistical associations of the IL-18 rs187238 G>C polymorphism with the susceptibility to TB under any of the genetic models (all P > 0.05). Country-stratified analysis results detected that the variants of IL-18 may be strongly enrolled in the risk of TB among populations in China (allele model: OR 1.19, 95 % CI 1.06-1.33, P = 0.003; recessive model: OR 1.54, 95 % CI 1.00-2.36, P = 0.048; homozygous model: OR 1.59, 95 % CI 1.09-2.33, P = 0.016; respectively), but not among populations in Iran, Korea and India (all P > 0.05). Current results provide strong evidence that IL-18 mutations may be evidently related to the occurrence and development of TB, especially for the rs1946518 C>A polymorphism among populations in China.

Genetic polymorphisms of Interleukin-18 are not associated with allograft function in kidney transplant recipients.

Interleukin 18 (IL-18) is a proinflammatory cytokine that plays a role in host defense by upregulating both innate and acquired immune responses. Analysis of IL18 polymorphisms may be clinically important since their roles have been recognized in a variety of inflammatory and autoimmune disorders. However, the role of this cytokine polymorphisms in kidney transplant still remains unclear. In this study, we evaluated the associations between IL18 polymorphisms and graft function assessed by creatinine clearance in kidney transplant recipients. A total of 82 kidney transplant recipients and 183 healthy controls were enrolled, and frequencies of alleles, genotypes and haplotypes for IL18 polymorphisms were determined and compared with creatinine clearance. The -607C/A (rs1946518) and -137C/G (rs187238) variant alleles in the IL18 gene were determined by polymerase chain reaction. In our study, no significant association was found between the IL18 variants and creatinine clearance (p > 0.05). Nonetheless, polymorphism analysis revealed an increase in the frequency of the IL18 major haplotype -607C/-137G in kidney transplant patients (odds ratio 2.57, 95% confidence interval 1.45-4.55, p = 0.0014). Finally, we found that IL18 polymorphisms did not influence the renal function and that IL18 haplotype -607C/-137G seems to be associated with kidney transplant recipients.

Polimorfismos genéticos de interleuquina 6 (IL6), IL6R e IL18: asociación con componentes del síndrome metabólico en niños chilenos con obesidad

Metabolic Syndrome (MS) is highly prevalent among obese children and adolescents and is considered a predictor for the development of type 2 diabetes mellitus and cardiovascular disease. Obesity is associated with an increase in circulating levels of interleukins 6 (IL6) and 18 (IL18), which in turn would depend on polymorphisms of IL6, IL6R and IL18 genes. To evaluate the association between genetic polymorphisms of IL6 (rs1800795, rs1800796 and rs1800797), IL6R (rs2228145) and IL18 (rs360719, rs187238 and rs204355) and MS and/or its components in a sample of Chilean obese children. These polymorphisms were genotyped in 259 obese children aged 10 ± 2 years with a body mass index of 26.1 ± 4.1 kg/m². Sixty eight had metabolic syndrome (26.3%). The association of their alleles, genotypes and haplotypes with the MS and its components was assessed. IL6, IL6R and IL18 variants showed no association with SM nor with any of the phenotypes that compose it. However, IL18 haplotypes (rs360719-rs187238-rs204355) TCT and CGT were associated with triglycerides ≤ 110 mg/dL and HDL < 40 mg/dL, respectively. IL6 and IL6R variants are not associated with MS or with any of its phenotypes. Although an association between IL18 haplotypes and certain MS component has been detected herein, it is necessary to replicate our findings in independent studies due to the low frequency of these allele combinations detected in our sample.

Association of IL-12, IL-18 variants and serum IL-18 with bladder cancer susceptibility in North Indian population

IL-12 and IL-18 are immunomodulatory cytokines that play important roles in host immune response against cancers. Variation in DNA sequence in gene promoter may lead to altered IL-18 production and/or activity, and hence can modulate an individual's susceptibility to BC. To test this hypothesis, we investigated the relationship of IL-18 gene promoter −137 G/C and −607C/A polymorphisms and IL12 (−16974) A/C with the risk of BC in North Indian population. Polymorphisms in IL-18 and IL-12 genes were analyzed in 200 BC patients and 200 age, ethnicity and sex-matched controls, using restriction fragment length polymorphism-polymerase chain reaction (PCR-RFLP) and amplification refractory mutation specific-polymerase chain reaction (ARMS) method. The concentrations of IL-18 in serum were determined by ELISA. Significant association was observed with IL18 (−137) G/C heterozygous genotype (GC) with 1.96 folds risk of BC as well at C allele carrier and variant C allele having 2 fold and 1.6 fold risk for BC respectively. IL18 (−607) C/A, heterozygous CA genotype also showed a high risk (OR=1.59) for BC. While IL12 (−16974) A/C heterozygote genotype and C allele carrier demonstrated reduced risk of BC. Hetero genotype of IL18 (−137) G/C was associated with risk of recurrence (HR=2.35) in superficial BC patients receiving BCG treatment thus showing least survival. The distributions of IL-18 gene haplotypes were not significantly different between patients and controls. Serum IL-18 levels were significantly higher in BC patients than in the healthy subjects (p=0.025). Serum IL-18 levels was also significantly associated with IL18 (−137) G/C in heterozygous genotype (GC) (p=0.048). Our results suggest that IL-18 gene polymorphism contributes to bladder cancer risk whereas IL-12 is protective. A relation between IL18 (−137) G/C in heterozygous genotype with elevated IL-18 serum level and bladder cancer risk has been registered in the present study.

Polymorphisms in the IL-18 and IL-12B genes and their association with the clinical outcome in Croatian patients with Type 1 diabetes

Genetic variants of IL-18 and IL-12B may be important in immunoregulatory abnormalities, observed in the patients with Type 1 diabetes mellitus (T1DM), that contribute to individual differences in response to a treatment. Therefore, we examined the significance of IL-18-137G/C, IL-18-607C/A, and IL-12B A/C polymorphisms in Croatians (187 patients, 236 controls), not only as factors that contribute to susceptibility to T1DM, but also as determinants of the clinical presentation of disease.The polymorphism screening has been performed using PCR sequence-specific primers (IL-18) or PCR-RFLP (IL-12B) approach. Results were evaluated by GraphPad Prism and Sigma Stat 3.5, Arlequin software and calculator for Hardy–Weinberg equilibrium.The genotype, allele and haplotype distribution were not statistically different between the patients and control subjects. The clinical parameter analysis revealed that patients with minor alleles at each locus, IL-18-137C/-607A, were significantly younger at T1DM onset than carriers of major alleles, IL-18-137G/-607C (20 vs 23.5years). Moreover, the concomitant presence of minor alleles not only of IL-18 but also of IL-12B, is associated with the risk of disease progression even at younger age. These patients developed diabetes at 16years of age, what is significantly earlier (p=0.044) compared to 25.5years of age in patients with common alleles IL-18-137G/-607C/IL-12B A. Furthermore, combined genotype analysis of IL-18 and IL-12B has pointed out that patients with CC/AA/AA genotype have the worst glucose control based on HbA1c (8.7%, range 6.8–13.1%).In conclusion, susceptibility to T1DM in Croatians is not strongly associated with IL-18-137/-607 and IL-12B polymorphisms. These SNPs are associated with the higher risk of earlier disease development and might be implicated in the effectiveness of glycemic control.

Impact of Interleukin-13 and -18 Promoter Polymorphisms in Health Care Workers with Natural Rubber Latex Allergy

It is a matter of debate whether single nucleotide polymorphisms (SNP) in the promoter region of interleukin (IL)-13, an IgE regulator, and IL-18, an inducer of immune responses, modulating the respective protein expression, are accompanied by an increased risk of atopy, allergic asthma, and total IgE levels. The suspected associations were noted in health care workers (HCW) with and without latex allergy. IL-13 (−1055C>T) and three IL-18 (−656T>G, −607C>A, −137G>C) SNP were studied in 523 HCW with natural rubber latex (NRL) exposure and diagnosis in the late 1990s. Three hundred and thirty-four HCW displayed NRL sensitization and allergic symptoms, 93 with latex-allergic asthma, and 189 HCW with neither symptoms nor NRL sensitization. SNP analyses were performed by real-time polymerase chain reaction (PCR) using newly developed LightCycler assays. Analysis of IL-13 −1055C>T by analysis of variance (ANOVA) revealed significantly elevated total IgE levels in HCW carrying the CT or TT variant compared with the CC variant. None of the studied SNP showed an association with NRL-specific IgE. The IL-18 variants −656GG and −607CC displayed 99.5% linkage disequilibrium. Frequencies of alleles −656GG and −607CC were elevated in HCW with NRL asthma (48.4%) compared with HCW without symptoms (37.6%). In contrast, IL-18 −137G>C variants displayed an overall homogenous distribution. The association between the IL-13 -1055T allele and elevated total IgE levels confirms the role of a genetic background for total IgE regulation. The studied IL-18 SNP demonstrated no significant association with the clinical outcome, total IgE, or specific IgE in HCW with natural rubber latex allergy.