Proinflammatory Cytokine Gene Polymorphisms Research Articles

Polymorphisms of the Proinflammatory Cytokine Genes Modulate the Response to NSAIDs but Not to Triptans in Migraine Attacks.

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (IL-1α, IL-1β, IL-1RN; IL-6 and TNF-α) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the TNF-α promoter (-308 A/G) and a lack of efficacy after NSAID administration (p < 0.01, OR 2.51, 95% CI: 1.33 < OR < 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the TNF-α gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack.

Proinflammatory Cytokine Polymorphisms and Severity of Periodontitis in a Cohort of Bulgarian Patients

Abstract In this manuscript we are discussing our research of the presence of single nucleotide polymorphisms (SNPs) of two proinflammatory cytokines – interleukin 17F (IF-17F) and interleukin 23 (IL-23) in a cohort of Bulgarian patients. The aim of the study was to investigate the presence of SNPs of IL-17F and IL-23 and to explore a relation between IL-23 and IL-17F and severity of periodontitis. In the study 83 individuals were included – 62 patients with severe periodontitis and 21 healthy participants. Detailed periodontal status was taken in order to estimate the diagnosis of each participant. A Real-Time PCR for determination of SNP of IL-17 and IL-23 was performed. The data was summarised and processed by the means of statistical analysis. The results showed that when testing individuals for SNP of IL-17F, three genotypes were detected – TT, CT, CC, with prevalence of the TT genotype. In regards to SNP of IL-23, the widespread distribution of GG genotype represents the major share among all individuals with only three representatives with GA genotype. Important tendencies about the severity of the periodontal disease with regards to the SNPs and their simultaneous presence were found. Conclusion: In the present study two proinflammatory cytokine gene polymorphisms were explored and studied in relation to the severity of the periodontal disease. Their distribution among the tested individuals was established and relation to major parameters of the periodontal disease was evaluated.

Imbalance of NK cell subpopulations and polymorphisms of proinflammatory cytokine genes in the pathogenesis of atherosclerosis

Understanding the pathogenetic mechanism of development and identifying trigger markers of the disease will significantly increase the efficiency of pre-nosological diagnosis and medical follow-up of patients. In this case, one should take into account the role of mutations in cytokine genes, which affect their biochemical activity and production level. The objective of the study was to investigate the role of mediators of acute and chronic inflammation (IL-17A, IL-1â, TNFá and IL-4), the ratio of natural killer cell subpopulations (CD56hiCD16-/CD56loCD16+) in pathogenesis of coronary atherosclerosis resulting into coronary heart disease.To analyze the results, an integrated approach was used, including molecular genetic methods such as polymerase chain reaction, typing of single-nucleotide substitutions in cytokine genes, isolation and cultivation of peripheral blood mononuclear cells, assessment of spontaneous and in vitro-induced production of immune system mediators, enzyme-linked immunosorbent assay, cytotoxic test, flow cytometry with monoclonal antibodies (Beckman Coulter, USA) to CD16, CD56 NK markers.The study included 130 residents of the North Caucasus, including the patients (n = 62) treated at the Cardiology Department of the Adyghe Republican Clinical Hospital (ARCB) with a verified diagnosis of ischemic heart disease (IHD), and a control group (n = 68), represented by unrelated healthy donors.Overexpression of cytokines in IHD patients was associated with distinct single nucleotide substitutions in certain genes. Studying a group of residents from the Republic of Adygeya, the authors experimentally established that harboring the 511C allele of the IL-1â gene (p < 0.0004; OR = 4.67), A197A of the IL-17A gene genotype (p < 0.04; OR = 3.88), G308 SNP of TNFá gene (p < 0.01; OR = 3.41), and 589T variant of IL-4 gene (p < 0.04; OR = 2.45) are associated with hyperproduction of the first-wave inflammatory mediators that increase the risk of developing ischemic heart disease. In atherosclerosis and associated cardiovascular diseases, we have noted a significant decrease in spontaneous and induced activity of natural killer cells involved in the utilization of “foamy cells”. The NK activity of peripheral blood mononuclear cell in patients with coronary heart disease is significantly reduced. In the IHD patients, an imbalance of phenotypically and functionally different CD56hiCD16-/CD56loCD16+ NK subpopulations with a predominance of CD56hiCD16- phenotype were revealed. Conclusions: Immuno-inflammatory mechanisms of evolving coronary atherosclerosis are associated with single-nucleotide substitutions, i.e., polymorphisms in the promoter regions of the IL-17A (G197A), IL-1 â (T511C), and TNFá (G308A), the known mediators of acute and chronic inflammation.Genetically determined overexpression of IL-17A, IL-1â, and TNFá, confirmed in experiments on evaluation of spontaneous and stimulated cytokine production in patients with CHD, together with reduced NK activity of РВМС, due to predominance of CD56hiCD16-, a subpopulation with high cytokine production, manifested by an increased pro-inflammatory component that triggers and provides long-term support to pathophysiological processes of atherosclerosis.

Association of Pro-inflammatory Cytokine Gene Polymorphism with Meniere's Disease in an Iranian Sample.

Meniere's disease (MD) is known as a rare chronic disorder of the inner ear with elevated serum levels of pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, Interleukin (IL)-1, and IL-6. This study aims to evaluate genes polymorphism in some pro-inflammatory cytokines in a group of Iranian MD patients compared to the healthy controls. In this case-control study, 25 MD patients and 139 healthy controls were enrolled. DNA was extracted from blood samples, and single nucleotide polymorphisms were detected using polymerase chain reaction with sequence-specific primers assay. MD patients and controls were examined in terms of allele, genotype, and haplotype frequency of pro-inflammatory cytokine genes. Only the frequencies of alleles A/G at position -238 in the promoter of the TNF-α gene differed significantly between MD patients and healthy controls. G to A allele ratio was 23 and 3.6 in MD and controls, respectively. In individuals with MD, genotype GG was found to be significantly more prevalent at position -238 of the TNF-α gene promoter sequence. In addition, the heterozygote AG variant of -238 A/G TNF-α gene polymorphism was lower in MD patients than controls. Compared to the control group, the haplotype TNF- (-308, -238) AG was higher in MD patients, although not statistically significant. This is the first study that we know of that evaluates the frequencies of pro-inflammatory cytokine genes in an Iranian MD sample. This study shows the association between TNF-α and susceptibility to MD.

Association Study between Proinflammatory Cytokine Gene Polymorphism and Risk of Recurrent Spontaneous Abortion

To investigate the correlation between inflammatory cytokine gene polymorphisms and the risk of recurrent miscarriage. A total of 120 patients with recurrent spontaneous abortion in our hospital between January 2019 and December 2020 were selected as the recurrent spontaneous abortion group and 120 healthy pregnant women with early pregnancy who visited the hospital during the same period were used as the control group and the genotype of interleukin-18 was detected by single nucleotide polymorphism typing technique and the validation method was Hardy Weinberg’s law of genetic equilibrium was used to verify the genotype of interleukin-18 and the relationship between interleukin-18 genotype and the risk of recurrent spontaneous abortion was analyzed by logistic method. The results showed that the level of interleukin-18 in the recurrent spontaneous abortion group was significantly higher than that in the control group (p 0.05); the interleukin-18 (rs1946519) and interleukin- 18(rs360717) in the control group The actual genotype frequencies of interleukin-18(rs1946519) and interleukin-18 (rs360717) in the control group were also not significantly different from the theoretical values (test values were 0.474 and 0.153, p>0.05); the genotypes of the rs1946519 and rs360717 loci showed significant differences and the recurrent spontaneous abortion group had significantly more A alleles than the control group (p<0.05); rs1946519 and rs360717 locus mutant cases showed significant differences in serum interleukin-17 levels, with AA and TT genotypes showing higher concentrations than other genotypes, respectively (p<0.05); the relative risk of recurrent spontaneous abortion risk in rs1946519 AG and AA gene carriers was 2.468 and 2.468 times higher than that of the GG allele, respectively. The relative risk of recurrent spontaneous abortion in rs360717 TC and TT gene carriers was 1.973 and 1.545 times higher than that of CC allele, respectively and all of them had higher risk of recurrent spontaneous abortion (p<0.05). The rs1946519 polymorphic allele G and rs360717 allele C mutations of interleukin-18 affect the serum hormone levels of patients and lead to an increased risk of recurrent spontaneous abortion in pregnant women. Therefore, interleukin-18 gene polymorphisms may be an important basis for the pathogenesis of recurrent spontaneous abortion and its treatment.

Impact of Proinflammatory Cytokine Gene Polymorphisms and Circulating CD3 on Long-Term Renal Allograft Outcome in Egyptian Patients

ABSTRACT The extant study aimed to explore the influence of two cytokines TNF-α − 308 and IFN-γ + 874 gene polymorphism on development of renal transplant rejection and to investigate the feasibility of Th1 cytotoxic immune reaction (CD3). It includes 152 kidney recipients were divided into two subgroups: 76 stable graft functions (SGF) and 76 allograft dysfunctions (AD) compared with 56 healthy individuals as control group. TNF-α − 308 G > A and IFN-γ + 874 A > T genetic polymorphisms were characterized using ARMS-PCR technique. CD3 protein expression was measured using ELISA Kit. The effect on transplant outcome was analyzed where, statistically significant differences of TNF-a-308 G/A were observed between AD group when compared to SGF group (OR = 0.296, 95% CI = 0.091–0.965, p = .031) in AG genotype (intermediate producer genotype). Also, AD group displayed a statistically significant increase of IFN-γ + 874 TT (high producer genotype) when compared to SGF group (OR = 0.290, 95% CI = 0.127–0.665, p = .003). The expression of CD3+ T lymphocytes in recipients with allograft dysfunction was statistically higher than that with stable allograft function and control groups (732 ± 76, 235 ± 51 and 442 ± 50) respectively and (p ≤ 0.001). In conclusion, IFN-γ + 874 T and TNF-α − 308 A alleles are risk alleles for renal transplant rejection and these two single nucleotide polymorphisms (SNPs) may be implicated in the tendency of rejection after renal transplantation. CD3 may be used as non-invasive biomarker in monitoring of rejection and avoid exposing patients for biopsy risks and sampling error.

Polymorphism of proinflammatory cytokine genes in girls predisposed to recurrent respiratory infections

Acute respiratory infections (ARI) are very common in children and often prompt parents to seek medical advice. Increased susceptibility to ARI is caused by a number of factors, including genetically determined imbalances in cytokine production. The aim of this study was to analyze the frequency of 6 clinically relevant polymorphisms of proinflammatory cytokine genes in girls predisposed to recurrent respiratory infections. The study was conducted in girls aged 7–17 years who were undergoing a routine medical checkup. A group of children with frequent respiratory infections was identified. The following polymorphisms were analyzed for possible associations with predisposition to frequent respiratory infections: IL1β T-31C (rs1143627), IL1β T-511C (rs16944), IL1β C-3953T (rs1143634), IL1β G-1473C (rs1143623); IL6 C-174G (rs1800795), and TNFα G-308A (rs1800629). For polymorphism detection, PCR and gel electrophoresis were used. The following alleles were found to be associated with an increased risk for recurrent respiratory infections in girls aged 7–17 years: С-31 (rs1143627) (OR = 2.05; CI: 1.16–3.64; р = 0.013) and С-511 (rs16944) (OR = 3.11; CI: 1.25–7.76; р = 0.013) of the IL-1β gene.

Influence of proinflammatory cytokine gene polymorphisms on the risk of COPD and the levels of plasma protein

IntroductionChronic obstructive pulmonary disease (COPD) is a complex and multifactorial disease involving systemic inflammation. Although certain genetic components have been implicated in the development and progression of this disease, few studies have examined the participation of polymorphisms in proinflammatory genes and the extent to which polymorphisms are related to plasma levels of cytokines involved in the inflammatory process. MethodsOf the 1125 smokers participating in the study, 438 had COPD, and 687 did not. We determined the genotype of 5 SNPs distributed in the genes: IL6, CXL8, CSF2, CCL1 and IL1B. The plasma protein expression of these genes was also evaluated and categorized according to genotype and the severity of COPD (GOLD grade). ResultsAn analysis using the codominant model showed an association between rs1818879 in IL6 and susceptibility to COPD (GA OR = 1.1, AA OR = 1.77; p < 0.01), as well as an association between rs25882 in CSF2 and a greater severity of the disease (TC OR = 1.84, CC OR = 3.62; p < 0.01). No association was found between the presence of certain alleles in the SNPs and the plasma levels of the corresponding proteins. ConclusionsThere are genetic polymorphisms related to susceptibility to COPD (rs1818879/A in IL6), as well as to the risk of greater severity of the disease (rs25882/T in CSF2). The presence of the alleles of interest did not significantly affect plasma levels of the codified proteins.

P065Polymorphisms in pro- and anti-inflammatory cytokine genes and HIV infection in North Indians

Aim Various candidate gene based studies on available specialized cohorts viz. viremic controllers, elite controllers, exposed uninfected individuals, rapid and slow progressor individuals support role of immunogenetic factors in defining HIV/AIDS outcome. In this context, the differential genetic influence of cytokine genes on immune response network can affect the establishment and spread of HIV infection; however information is limited on Indian populations. Therefore, here we aimed to explore the largely unknown genetic influence of various pro (IL-1, IL-2, IFN-γ etc.) and anti inflammatory (IL-4, IL-10, TGF-β etc.) cytokine gene polymorphisms on HIV infection, particularly in North Indian population. Methods We enrolled a total of 157 HIV patients, 130 healthy and 27 exposed uninfected healthy controls from the North Indian states after obtaining the institutional ethical approval and participants’ informed consent. Evaluation of 22 functionally relevant single nucleotide polymorphisms in 13 cytokine and their receptor genes was performed by genotyping using PCR-SSP based approach. Appropriate softwares and statistical tests were used (chi square and Fishers Exact test wherever applicable) for comparison. Results Frequencies of most of the analyzed variants were statistically indifferent between HIV patients and uninfected healthy controls at the allelic, genotypic and haplotypic levels. Significantly higher allelic frequencies of IL-1α -889 T and IL-4 -1098 T were observed in HIV patients, while IL-1α -889 CC, IL-4 -1098 GG and IL-6 nt565 AA genotypes were observed significantly lower as compared healthy uninfected controls. Conclusions This study represents the first report that highlights the influence of various cytokine gene polymorphisms in context of HIV infection in the North Indians. The observed associated variants are known to have functional relevance towards modulating the inflammatory mileu.

Polymorphisms in proinflammatory cytokine genes, effect on gene expression and association with preterm delivery in Saudi females

Genetic polymorphism in proinflammatory cytokine genes may be associated with the etiology of preterm birth (PTB). The current study was designed with the aim to explore the association of genetic polymorphisms and mRNA expression of IL-1α, IL-1β, and TNF-α gene with preterm birth in the Saudi population. Genotyping of genomic DNA of 50 PTB patients and an equal number of controls were carried out using TaqMan Genotyping assay kits. Gene expression of each gene was carried out using quantitative RT-PCR. The cytokine levels in the serum of PTB patients and controls were measured by ELISA. A statistically significant association was observed between the rs361525 alleles (G and A) of TNF-α and PTB, where the mutant A allele was significantly protective against PTB development (OR= 0.362; χ2=4.31; p=0.038). The gene expression of all studied genes (IL1α, IL-1β, IL-6, and TNF-α) was higher in the PTB patients, but the results reached significance only for IL-1β (p=0.035). Elevated gene expression was also evident from the level of these proteins in plasma, where the level of IL1α, IL-β were significantly higher in the serum of PTB patients compared to the controls, however, IL6 and TNF-α were significantly lower despite higher gene expression. For IL6, the lower level could be due to tocolytic treatment that was given to all women suffering from PTB. Receiver operating curves (ROC) were drawn for the studied cytokines. In conclusion, this study revealed that rs361525 polymorphism plays a role as a protective marker for PTB and the levels of IL-1α, IL-6, TNF- α can be used as predicative biomarkers for PTB I Saudi women.

Genetic association of pro-inflammatory cytokine gene polymorphisms with coronary artery disease (CAD) in a North Indian population

BackgroundCytokines regulate the expression of inflammatory molecules which destabilize the atheromatic plaques. This study focuses on studying the association of inflammatory cytokine polymorphisms like TNF-α −308 (G/A), TNF-β +252 (A/G), IL-6 −174 (G/C) and IL-6 −597 (G/A), and IFN-ɣ +874 (T/A) with coronary artery disease (CAD) among north Indian patients. Materials and methods143 CAD and 137 normal healthy controls were recruited in this study. DNA extraction was carried out by high salting out method. TNF-α −308 (G/A) (rs1800797), TNF-β +252 (A/G) (rs909253), IL-6 −174 (G/C) (rs1800795), IL6 −597 (G/A) (rs1800797), and IFN-ɣ +874 (T/A) (rs2430561) SNPs were genotyped by TaqMan®SNP genotyping assays. Different statistical analyses were performed using SPSS v 22.0 and SNPStats. p≤0.05 was considered significant. ResultsSignificant risk association with CAD was found for TNF-α −308 (G/A) “A” allele (OR=5.6, CI 1.8–17.4, p=0.001) and TNF-β +252 (A/G) “G” allele (OR=3.4, CI=1.9–6.0, p<0.001). However, no statistical significance was found for IL-6 −174 (G/C) or IL6 −597 (G/A), with CAD. TNF-α −308 (G/A), and TNF-β +252 (A/G) haplotype “GG” “AG” increased CAD risk significantly (GG haplotype, adjusted OR=2.6, CI 1.4–5.0, p=0.003 and AG haplotype OR=8.5, CI 2.2–33.35, p=0.002) after adjustments for age, sex, TC, TG, HDL, APOB, smoking and diet. DiscussionThe present study found significant risk association for TNF-α −308 (G/A), and TNF-β +252 (A/G) genotypes, alleles and haplotypes, with CAD in a North Indian population.

Impact of TNF-α (rs1800629) and IL-6 (rs1800795) Polymorphisms on Cognitive Impairment in Asian Breast Cancer Patients.

ObjectiveExpression of pro-inflammatory cytokines is influenced by single nucleotide polymorphisms (SNPs) in the promoter regions of the pro-inflammatory cytokine genes, and cytokines are associated with the occurrence of post-chemotherapy cognitive impairment. Hence, the aim of this study was to evaluate the associations between two common pro-inflammatory cytokine gene polymorphisms namely, IL6-174 (rs1800795 G>C) and TNF-308 (rs1800629 G>A), and chemotherapy-associated cognitive impairment (CACI) among Asian early-stage breast cancer patients. In addition, the differential effect of these SNPs on plasma IL-6 and TNF-α levels, and the associations of plasma IL-6 and TNF-α levels with CACI were also assessed.MethodsAsian early-stage breast cancer patients (Stage I to III) receiving chemotherapy were prospectively recruited from two cancer centers in Singapore. Patients' cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) and an objective computerized battery, Headminder™ at three-time points. Plasma IL-6 and TNF-α levels were analyzed using the multiplex immunoassay, and genotyping was performed using Sanger sequencing. Regression analyses and generalized estimating equation were utilized for statistical analysis.ResultsA total of 125 patients were included (mean age: 50.3; Chinese: 80.8%; post-menopausal: 48.0%; 68.0% received anthracycline-based chemotherapy). 36.8% patients experienced self-perceived cognitive impairment, detected in memory (32.8%) and attention (34.2%) domains. Patients with higher levels of anxiety (p<0.001) and insomnia (p = 0.003) also reported more self-perceived cognitive impairment. Higher plasma concentrations of IL-6 were associated with greater severity of self-perceived cognitive impairment (p = 0.001). Polymorphisms of cytokine genes were not associated with expression of plasma cytokines.ConclusionPresent findings further contribute to the growing evidence that supports the role of the pro-inflammatory cytokine IL-6 in the occurrence of cognitive impairment post-chemotherapy. However, genetic polymorphism of these cytokines did not play a major role to the cytokine fluctuations as well as cognitive impairment in this cohort. With an increasing evidence to support the cytokine hypothesis, future studies should investigate the role of anti-inflammatory agents in mitigating the cognitive impairment associated with chemotherapy.

Pro-inflammatory cytokines and their epistatic interactions in genetic susceptibility to schizophrenia.

BackgroundIn schizophrenia, genetic background may provide a substrate for intrinsic maldevelopment of the brain through environmental influences, by recruiting neurotrophic factors and cytokines, to trigger the changes that lead to impaired neuronal functions. Cytokines being the key regulators of immune/inflammatory reactions are also known to influence the dopaminergic, noradrenergic, and serotonergic neurotransmission. Therefore, functional polymorphisms in cytokine genes may result in imbalances in the pro- and anti-inflammatory cytokine production.MethodsWe screened polymorphisms in pro- and anti-inflammatory cytokine genes using a case-control association study in a South Indian population. The role of allele, genotype, haplotype, and diplotypes of these cytokine genes and their epistatic interactions were assessed in contributing to the risk of developing schizophrenia. Meta-analysis for the reported associations was also monitored for global significance.ResultsThe pro-inflammatory cytokine gene polymorphisms in IL1Ars1800587, IL6rs1800796, TNFArs361525, and IFNGrs2069718 were associated with schizophrenia. The study also provides significant evidence for strong epistatic interactions among pro-inflammatory cytokine genes IL6 and IFNG in the development of schizophrenia. In silico analysis suggested that associated risk variants were indicative of altered transcriptional activity with higher production of IL1α, IL-6, TNF-α, and IFN-ɤ cytokines. Meta-analysis indicated heterogeneity among study population while IL1Ars1800587 was found to be globally significant.ConclusionsIt is important to identify the nature of inflammatory response that can be amplified by the environment, to influence either Th1 response or Th2 response. The associated functional variants in the study are involved with increased expression resulting in higher production of the pro-inflammatory cytokines IL-1α, IL-6, TNF-α, and IFN-γ. The interaction of immunological stressors with these high producer alleles of pro-inflammatory cytokines may suggest that even a lower threshold may be sufficient to induce a resultant chronic effect on the psycho-social and environmental stressors that may result in the development and pathogenesis of schizophrenia. Understanding environmental factors that influence the expression of these pro-inflammatory cytokine genes or their interaction can possibly help in dissecting the phenotypic variation and therapeutic response to antipsychotics in schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0569-8) contains supplementary material, which is available to authorized users.

Kidney Transplantation, Polymorphisms of IL-18, and Other Pro-Inflammatory Genes and Late Post-Transplant Outcome

BackgroundFunctional polymorphisms of molecules involved in immune-mediated mechanisms of allograft rejection could be predictive of increased risk for early and late post-transplant complications. In the past years, the challenge for long-term graft survival in kidney recipients is the implementation of personalized approaches. In this study, effects of interleukin (IL)-18–137G/C (rs187238), –607C/A (rs1946518), and other pro-inflammatory cytokine gene polymorphisms (tumor necrosis factor [TNF]-α–308G/A, rs1800629, IL-6–174G/C, rs1800795, and interferon [IFN]-γ+874A/T, rs2430561) on the main post-transplant risk parameters and diseases (metabolic, cardiovascular, infective, and chronic allograft rejection) were assessed in kidney-transplanted patients. MethodsOne hundred seventy-nine transplanted patients were retrospectively analyzed for clinical and biochemical parameters and onset of post-transplant complications. Taqman allelic discrimination and PCR-SSP (polymerase chain reaction-sequence specific primers) techniques were used for genotyping. ResultsNo predictive effects of allele and genotypes of IL-18–607C/A, TNF-α–308G/A, IL-6–174G/C, and IFN-γ+874A/T gene polymorphisms and onset of risk factors and late complications were evidenced. However, Kaplan-Meier analysis evidenced a weak effect of IL-18–137G/C genotypes on graft survival. ConclusionsAnalyzing associations between some pro-inflammatory cytokine gene polymorphisms and onset of the most relevant risk factors and late complications of kidney transplant, results suggested a possible impact of IL-18–137G/C genotypes on graft survival, which deserves further studies.

Association of single nucleotide polymorphisms in pro-inflammatory cytokine and toll-like receptor genes with pediatric hematogenous osteomyelitis.

Hematogenous osteomyelitis (HO) is a bone infection wherein bacteria penetrate to the bone through the blood stream. Several single nucleotide polymorphisms (SNPs) have been associated with susceptibility to infectious diseases. In this study, we investigated the contribution of SNPs in interleukin (IL)-1B1 (rs16944), IL1A (rs1800587), IL1B (rs1143634), toll-like receptor (TLR)-2 (rs3804099), TLR4 (rs4986790), TLR4 (rs4986791), IL1R (rs2234650), tumor necrosis factor (TNF)-α (rs1800629), TNF (rs361525), and IL1RN (rs315952) towards the development of HO in Saudi patients and compared to healthy controls. Fifty-two patients diagnosed with HO and 103 healthy individuals were genotyped. The frequencies of genotypes GG (rs16944) and AA (rs16944) were lower and higher in patients [odds ratio (OR) = 0.34, Pc = 0.05] and controls (OR = 1.33, Pc = 0.05), respectively, suggesting that SNPs at this locus could alter HO susceptibility. In addition, the patients and controls exhibited lower and higher frequencies of the alleles G (rs16944) (OR = 0.43, Pc = 0.007) and A (rs16944) (OR = 2.32, Pc = 0.007), respectively. The expression of alleles C (rs3804099) and T (rs3804099) were higher in patients (OR = 2.05, Pc = 0.04) and controls (OR = 0.49, Pc = 0.04), respectively. In conclusion, SNPs at rs16944 and rs3804099 were found to be associated with HO in the Saudi population.

Роль полиморфизма гена Il-1β в развитии фебрильных приступов у детей (обзор)

This review provides information on the definition of febrile seizures in children, presents modern data on the dependence of the genetic predisposition to IL-Ιβ gene mutations and development of febrile seizures in children. Purpose of the review is analysis of available publications devoted to the study of the role of IL-Ιβ polymorphism in the development of febrile seizures in children. The literature search included available full-text publications in Russian and English databases. It was found that febrile seizures are characteristic for children from 6 months to 3 years. The causes of seizures still serve as a subject of debate. Family history of febrile seizures in the development is most important risk factor. Positive family history can be detected in 25-40% of patients. Components of the immune response may play a role in the pathogenesis of febrile seizures. One factor is a pro-inflammatory cytokine gene polymorphism of interleukin-ΐβ (IL-Ιβ). The analysis of the literature demonstrates the need for a detailed study of the genetic causes of febrile seizures in children, especially in patients with a positive family history.

Cytokine gene polymorphisms, cytokine levels and the risk of colorectal neoplasia in a screened population of Northeast Scotland.

Cytokine gene polymorphisms modify expression and their circulating protein levels reflect inflammatory response. Chronic inflammation plays a key role in the pathogenesis of colorectal neoplasia (CRN) associated with inflammatory bowel disease, but it is not clear whether inflammation is a cause or an effect of tumours in sporadic CRN. We therefore investigated the association of cytokine gene polymorphisms and circulating cytokine levels on the risk of CRN in Northeast Scotland, which has a high incidence of CRN. We recruited two groups of patients from a screening colonoscopy cohort, either preprocedure or 3-24 months postprocedure. Participants with CRN were compared with participants with no evidence of CRN (controls). Blood-derived DNA was used to genotype polymorphisms in IL1B, IL1-RN, IL6, IL8, IL10, PTGS2 and TNFA genes. Circulating levels of high-sensitivity C-reactive protein and six cytokines [interleukin-1β (IL-1β), IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-α (TNF-α)] were measured. To examine the effect of CRN resection on marker levels, we used propensity score matching. A total of 884 patients were eligible for analysis, including 388 CRN cases and 496 controls. Cases were older (mean age 64 vs. 62 years, P<0.01) and more likely to be men (67 vs. 55%, P<0.001). Controls were more likely to be regular users of NSAID (P<0.0001). Compared with homozygous carriage of respective common alleles, proinflammatory CC genotypes of IL1B-31C>T [odds ratio (OR) (95% confidence interval (CI) 1.68 (1.03-2.73)] and PTGS2-765 C>G [OR (95% CI) 2.97 (1.05-8.46)] were each associated with an increased risk of CRN. Conversely, carriage of the A allele of IL8-251A>T was associated with a lower risk of CRN compared with the TT genotype [ORs (95% CI) 0.60 (0.41-0.86) for heterozygous, 0.88 (0.57-1.37) for homozygous, and 0.68 (0.48-0.95) for heterozygous and homozygous combined]. Compared with postprocedure cases, IL8, TNF-α and C-reactive protein levels were significantly higher in preprocedure cases, but IL4 and IL10 protein levels were significantly lower. Proinflammatory cytokine gene polymorphisms in IL1B-31 and PTGS2-765 increase the risk of developing CRN. Levels of proinflammatory IL8, TNF-α and C-reactive protein markers are significantly higher while CRN is in situ. Along with the NSAID findings, these data point to inflammation as an underlying pathogenetic mechanism in CRN.

Association of combinations of interleukin-10 and pro-inflammatory cytokine gene polymorphisms with dengue hemorrhagic fever

Pro-inflammatory and anti-inflammatory cytokines have been shown to play an important role in dengue disease pathogenesis. In the present study, to find out whether single nucleotide polymorphisms (SNPs) in the pro-inflammatory and anti-inflammatory cytokine genes are associated with dengue disease severity, SNPs in TNF, IFNG, IL1B, IL8, IL0, IL17A and IL17F genes were investigated using polymerase chain reaction based methods in 132 dengue (DEN) cases [87 dengue fever (DF), 45 dengue hemorrhagic fever (DHF) cases] and 108 apparently healthy controls (HC) from Pune, Maharashtra, western India. Under recessive genetic model (C/C vs. T/T+T/C), the TNF rs1799964 C/C genotype was significantly associated with DEN [P=0.014, OR with 95% CI 3.07 (1.18–7.98)]. Frequency of T/C genotype of IL17F rs763780 was significantly lower in DEN group as compared to HC [P=0.033, OR with 95% CI 0.43 (0.19–0.95)]. Under overdominant genetic model (A/T vs. A/A+T/T), IL8 rs4973 A/T genotype was negatively associated with DHF compared to HCs [p=0.029, OR with 95% CI 0.43 (0.20–0.93)]. Under overdominant genetic model, A/G genotype of IL10 rs1800871 was significantly negatively associated with DHF compared to DF cases [p=0.014, OR with 95% CI 0.35 (0.15–0.84)]. Significantly higher frequency of the combined genotype IL10 A/A-IFNG A/T and lower frequency of the combined genotypes IL10 A/G-IL1B A/A, IL10 A/G-IL8 A/T and IL10 A/G-IL17F T/T were observed in DHF cases compared to DF. The results suggest that heterozygous genotypes of IL8 rs4973 and IL10 rs1800871 are associated with reduced risk of DHF. Combinations of IL10 rs1800871 and pro-inflammatory cytokine genotypes influence the risk of DHF.

Cytokine gene polymorphism (interleukin-1β +3954, Interleukin-6 [-597/-174] and tumor necrosis factor-α -308) in chronic periodontitis with and without type 2 diabetes mellitus.

Pro-inflammatory cytokine gene polymorphisms are potential candidates for susceptibility for both type 2 diabetes mellitus (DM) and chronic periodontitis (CHP). This study explored the association of interleukin-1 beta (IL-1 β) +3954, interleukin-6 (IL-6) -597/-174 and tumor necrosis factor-alpha (TNF-α) -308 single nucleotide polymorphisms in CHP with and without type 2 DM in Malayalam speaking subjects of Dravidian ethnicity. This case control study consisted of 51 chronic periodontitis with type 2 diabetes mellitus (CHPDM) and 51 CHP patients as cases and 51 healthy subjects as controls. Polymorphisms were identified by polymerase chain reaction amplification followed by restriction enzyme digestion and gel electrophoresis. IL-1 β (+3954) TT genotype and T allele were significantly associated with CHPDM group when compared with CHP (P = 0.001), whereas CC genotype and allele C was higher in CHP subjects (P = 0.001). For IL-6 (-597) frequency of genotype GA/AA (P = 0.04) and allele A (P = 0.01) was lower in CHPDM group, and for TNF-α -308 the frequency of genotype GA (P = 0.01) and allele A (P = 0.01) was higher in CHP subjects when compared with controls. In Malayalam speaking Dravidian population, IL-6 (-597) genotype GA/AA and allele A appears to be protective for CHP with type 2 DM. Allele C of IL-1 β +3954 and allele A of TNF-α -308 appears to be risk factors for CHP individuals.

Association of pro-inflammatory cytokine gene polymorphisms with schizophrenia in South Indian population

Background Schizophrenia is a severe and debilitating mental illness. Around 0.26% of people in South India suffer from schizophrenia. It is a complex disorder which may involve multiple genes with mild to moderate effect and nongenetic risk factors like environmental and psychological assaults. Cytokines, regulators of immune/inflammatory reactions and brain development, emerge as part of a common pathway of genetic and environmental components of schizophrenia. Our study explored the association of polymorphisms in cytokine genes with schizophrenia, the interaction of these genes in the causation of the disease and the population genetics of cytokine gene polymorphisms.