Cytokine Gene Variants Research Articles

Wilson's Disease-Crossroads of Genetics, Inflammation and Immunity/Autoimmunity: Clinical and Molecular Issues.

Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD.

Analysis of the Association of IL-1A, IL-1B, and IL-1RN Genetic Polymorphisms with Peri-implantitis in a Portuguese Population.

To investigate whether genetic variations in cytokine genes involved in the pathogenesis of peri-implantitis are associated with the occurrence of peri-implantitis, an issue that remains controversial and may vary according to the population evaluated. A cross-sectional analytical study was carried out on 102 Caucasian Portuguese individuals who were divided into two groups: (1) 43 individuals with peri-implantitis and (2) 59 individuals with good peri-implant health. Samples from the buccal mucosa were obtained, and genetic analysis was performed using the real-time polymerase chain reaction (PCR) technique for IL-1A and IL-1B and PCR for IL-1RN. The IL-1A-889 C/T polymorphism presented with a higher prevalence of the less common allele (T allele) in patients with peri-implantitis (27.9%) than in healthy patients (16.9%), but without statistical significance (P = .060). For the IL-1B+3954 C/T and IL-1RN (variable number of tandem repeats [VNTR]) polymorphisms, analysis revealed that the allele and genotype frequencies did not differ significantly between groups. There was a significant association between a history of periodontitis and peri-implantitis (P = .020). The evaluated genetic polymorphisms had no influence on the occurrence of peri-implantitis in the study population. Further research into genetic variations in different populations is needed to elucidate the role of genetic factors in the onset and progression of peri-implant disease.

Effects of SNPs on TNF-α and IL-10 cytokine expression in TB and HIV patients in the Capricorn district, Limpopo Province, South Africa.

The impact of Tuberculosis (TB) places an immense burden on the health care system. Infection with Human Immunodeficiency Virus (HIV) is a significant risk factor in the development and progression of TB disease. Single Nucleotide Polymorphisms (SNPs) in the promoter region of Interleukin-10 (IL-10) and Tumour Necrotic Factor-Alpha (TNF-α) may play a major role in the disease mechanism and understanding these mechanisms might prove to be a useful diagnostic tool in evaluating the immune regulation and progression of the disease. This study aimed to determine the relationship between cytokine levels and gene variants of Interleukin-10 and Tumour Necrotic Factor Alpha in TB and HIV-infected participants. Cytokine levels were determined by ELISA, and SNPs were determined by MassArray®. The levels of TNF-α were higher in the TB group than the HIV (p < 0.001) and TB-HIV (p = 0.011) groups, but similar to the TNF-α levels in the control group. In the HIV group, IL-10 levels were higher than those of the TB (p < 0.001) and control groups (p = 0.039), whereas there was no difference between the IL-10 levels in the HIV and the TB-HIV infection groups. The ratio was determined and there were no differences between the four infection groups. In this study, no associations were detected between the circulating plasma levels of TNF-α and IL-10 and their genotypes. Our data showed that the gene variants were not associated with circulating plasma levels of TNF-α and IL-10 in our study population. A pro-inflammatory environment was found in the TB and TB-HIV groups, which is suggesting of bacterial clearance, while an anti-inflammatory environment was found in the HIV group, which suggests the suppression of viral replication.

Association of Cytokine Gene Polymorphisms and Their Impact on Active and Latent Tuberculosis in Brazil's Amazon Region.

Some genetic variations in cytokine genes can alter their expression and influence the evolution of Mycobacterium tuberculosis (Mtb) infection. This study aimed to investigate the association of polymorphisms in cytokine genes and variability in plasma levels of cytokines with the development of tuberculosis (TB) and latent tuberculosis infection (LTBI). Blood samples from 245 patients with TB, 80 with LTBI, and healthy controls (n = 100) were included. Genotyping of the IFNG +874A/T, IL6 -174G/C, IL4 -590C/T, and IL10 -1082A/G polymorphisms was performed by real-time PCR, and cytokine levels were determined by flow cytometry. Higher frequencies of genotypes AA (IFNG +874A/T), GG (IL6 -174G/C), TT (IL4 -590C/T), and GG (IL10 -1082A/G) were associated with an increased risk of TB compared to that of LTBI (p = 0.0027; p = 0.0557; p = 0.0286; p = 0.0361, respectively) and the control (p = <0.0001, p = 0.0021; p = 0.01655; p = 0.0132, respectively). In combination, the A allele for IFNG +874A/T and the T allele for IL4 -590C/T were associated with a higher chance of TB (p = 0.0080; OR = 2.753 and p < 0.0001; OR = 3.273, respectively). The TB group had lower levels of IFN-γ and higher concentrations of IL-6, IL-4, and IL-10. Cytokine levels were different between the genotypes based on the polymorphisms investigated (p < 0.05). The genotype and wild-type allele for IFNG +874A/T and the genotype and polymorphic allele for IL4 -590C/T appear to be more relevant in the context of Mtb infection, which has been associated with the development of TB among individuals infected by the bacillus and with susceptibility to active infection but not with susceptibility to latent infection.

Association of Single Nucleotide Polymorphisms of Cytokine Genes with Depression, Schizophrenia and Bipolar Disorder.

Immune gene variants are known to be associated with the risk of psychiatric disorders, their clinical manifestations, and their response to therapy. This narrative review summarizes the current literature over the past decade on the association of polymorphic variants of cytokine genes with risk, severity, and response to treatment for severe mental disorders such as bipolar disorder, depression, and schizophrenia. A search of literature in databases was carried out using keywords related to depressive disorder, bipolar disorder, schizophrenia, inflammation, and cytokines. Gene lists were extracted from publications to identify common genes and pathways for these mental disorders. Associations between polymorphic variants of the IL1B, IL6, and TNFA genes were the most replicated and relevant in depression. Polymorphic variants of the IL1B, IL6, IL6R, IL10, IL17A, and TNFA genes have been associated with schizophrenia. Bipolar disorder has mainly been associated with polymorphic variants of the IL1B gene. Interestingly, the IL6R gene polymorphism (rs2228145) was associated with all three diseases. Some cytokine genes have also been associated with clinical presentation and response to pharmacotherapy. There is also evidence that some specific polymorphic variants may affect the expression of cytokine genes. Thus, the data from this review indicate a link between neuroinflammation and severe mental disorders.

Molecular Evaluation of the Impact of Polymorphic Variants in Apoptotic (Bcl-2/Bax) and Proinflammatory Cytokine (TNF-α/IL-8) Genes on the Susceptibility and Progression of Myeloproliferative Neoplasms: A Case-Control Biomarker Study

The regulation of apoptosis (the programmed cell death) is dependent on the crucial involvement of BCL2 and BAX. The Bax-248G>A and Bcl-2-938 C>A polymorphic variations in the promoter sequences of the Bax and Bcl-2 gene have been recently associated with low Bax expression, progression to advanced stages, treatment resistance, and shortened overall survival rate in some hematological malignancies, including chronic myeloid leukemia (CML) and other myeloproliferative neoplasms. Chronic inflammation has been linked to various stages of carcinogenesis wherein pro-inflammatory cytokines play diverse roles in influencing cancer microenvironment leading to cell invasion and cancer progression. Cytokines such as TNF-α and IL-8 have been implicated in cancer growth in both solid and hematological malignancies with studies showing their elevated levels in patients. Genomic approaches have in recent years provided significant knowledge with the regard to the association of certain SNPs (single nucleotide polymerphisms) either in a gene or its promoter that can influence its expression, with the risk and susceptibility to human diseases including cancer. This study has investigated the consequences of promoter SNPs in apoptosis genes Bax-248G>A (rs4645878)/Bcl-2-938C>A (rs2279115) and pro-inflammatory cytokines TNF-α rs1800629 G>A/IL-8 rs4073 T>A on the risk and susceptibility towards hematological cancers. The study design has 235 individuals both male and female enrolled as subjects that had 113 cases of MPDs (myeloproliferative disorders) and 122 healthy individuals as controls. The genotyping studies were conducted through ARMS PCR (amplification-refractory mutation system PCR). The Bcl-2-938 C>A polymorphism showed up in 22% of patients in the study, while it was observed in only 10% of normal controls. This difference in genotype and allele frequency between the two groups was significant (p = 0.025). Similarly, the Bax-248G>A polymorphism was detected in 6.48% of the patients and 4.54% of the normal controls, with a significant difference in genotype and allele frequency between the groups (p = 0.048). The results suggest that the Bcl-2-938 C>A variant is linked to an elevated risk of MPDs in the codominant, dominant, and recessive inheritance models. Moreover, the study indicated allele A as risk allele which can significantly increase the risk of MPDs unlike the C allele. In case of Bax gene covariants, these were associated with an increased risk of MPDs in the codominant inheritance model and dominant inheritance model. It was found that the allele A significantly enhanced the risk of MPDs unlike the G allele. The frequencies of IL-8 rs4073 T>A in patients was found to be TT (16.39%), AT (36.88%) and AA (46.72%), compared to controls who were more likely to have frequencies of TT (39.34%), AT (37.70%) and AA (22.95%) as such, respectively. There was a notable overrepresentation of the AA genotype and GG homozygotes among patients compared to controls in TNF-α polymorphic variants, with 6.55% of patients having the AA genotype and 84% of patients being GG homozygotes, compared to 1.63% and 69%, respectively in controls. The data from the current study provide partial but important evidence that polymorphisms in apoptotic genes Bcl-2-938C>A and Bax-248G>A and pro-inflammatory cytokines IL-8 rs4073 T>A and TNF-α G>A may help predict the clinical outcomes of patients and determine the significance of such polymorphic variations in the risk of myeloproliferative diseases and their role as prognostic markers in disease management using a case-control study approach.

Impact of inflammatory cytokine and adipokine gene variations in the development of HIV-associated lipodystrophy.

Cytokines affect lipid and glucose metabolism and also alter the body's habitus. They play a role in the development of lipodystrophy syndrome. Adipocytes secrete the pro-inflammatory cytokines IL-1, TNF-α and IL-6. The plasma cytokine concentration is associated with the percentage and distribution of fat tissue in the body. The metabolic disturbances are strongly associated with increased levels of pro-inflammatory cytokines (IL-1, IL-6 and TNF-α). Plasma levels of cytokines such as TNF-α, IL-6 and leptin were found to be increased while plasma resistin levels were found to be variable in patients suffering from obesity and type II diabetes mellitus. Until now, limited information has been available on the polymorphism of cytokine and adipokine genes in patients of HIV-associated lipodystrophy (HIVLD), which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. Hence, we studied the association of cytokine and adipokine gene polymorphisms in various diseases and their impact on HIVLD. We carry out an extensive search using several databases, including PubMed, EMBASE and Google Scholar. The distribution of cytokine and adipokine gene polymorphisms and their expression levels varied among various populations. We examined the variants of cytokine and adipokine genes, which can contribute to individual variations in susceptibility to metabolic diseases, especially to HIVLD. In the current review, we present a brief account of the risk factors of HIVLD, the pathogenesis of HIVLD and the polymorphism of cytokine and adipokine genes in various diseases with special reference to their impact on HIVLD.

Age and Cytokine Gene Variants Modulate the Immunogenicity and Protective Effect of SARS-CoV-2 mRNA-Based Vaccination.

The introduction of anti-SARS-CoV-2 vaccines in late 2020 substantially changed the pandemic picture, inducing effective protection in the population. However, individual variability was observed with different levels of cellular response and neutralizing antibodies. We report data on the impact of age, gender, and 16 single nucleotide polymorphisms (SNPs) of cytokine genes on the anti-SARS-CoV-2 IgG titers measured 31 and 105 days after administration of the second dose of BNT162b2 vaccine to 122 healthy subjects from the health care staff of the Palermo University Hospital, Italy. The higher titers at 31 days were measured in the younger subjects and in subjects bearing T-positive genotypes of IL-1R1 rs2234650 or the GG homozygous genotype of IL-6 rs1800795 SNP. T-positive genotypes are also significantly more common in subjects with higher titers at day 105. In addition, in this group of subjects, the frequency of the CT genotype of IL-4 rs2243250 is higher among those vaccinated with higher titers. Moreover, these SNPs and TNFA rs1800629 are differently distributed in a group of subjects that were found infected by SARS-CoV-2 at day 105 of evaluation. Finally, subjects that were found to be infected by SARS-CoV-2 at day 105 were significantly older than the uninfected subjects. Taken together, these data seem to suggest that age and polymorphisms of key cytokines, which regulate inflammation and humoral immune response, might influence the magnitude of the antibody response to vaccination with BNT162B2, prompting speculation about the possible benefit of a genetic background-based assessment of a personalized approach to the anti-COVID vaccination schedule.

Interleukin-10 promoter variability is associated with the susceptibility, severity, and clinical outcomes of aplasitc anemia in Han-Chinese population.

Acquired aplastic anemia (AA), a heterogeneous bone marrow (BM) failure disease, is mainly mediated by the immune destruction of hematopoietic stem cells (HSCs). Given the predominant role of immunosuppressive therapy (IST) in AA, it is sensible to theorize that variants of cytokine genes might affect the outcome of IST. In this study, we analyzed three single nucleotide polymorphisms (SNPs) of interleukin (IL)-10 gene in promoter region to clarify their relationship with susceptibility, clinical efficacy and prognosis of AA. We observed that CT genotype of IL-10 rs1800896 was associated with a decreased risk of AA (adjusted OR=0.541 [95% CI 0.295-0.993], p=.047). Besides, the disease severity differed considerably by IL-10 gene promoter genotypes and alleles. Furthermore, IL-10 SNPs influenced efficacy of IST, with unfavorable response exhibited by rs1800871 and rs1800872 in dominant models (GG + AG vs. AA, adjusted OR=0.409 [95% CI 0.178-0.943, p=.036] for rs1800871 and GG + GT vs. TT, adjusted OR=0.396 [95% CI 0.173-0.909, p=.028] for rs1800872, respectively). The polymorphisms of IL-10 promoter region were informatively genetic risk factors which might be conducive to the insights into the mechanisms of AA and the design of individual regimens.

GENETIC VARIANTS AND SERUM PROFILES OF CYTOKINES IN COVID-19 SEVERITY.

Background: Patients with severe coronavirus disease 2019 (COVID-19) are at an increased risk of acute respiratory distress syndrome and mortality. This is due to the increased levels of pro-inflammatory cytokines that amplify downstream pathways that are controlled by immune regulators. Objective: This study aimed to investigate the association between cytokine genetic variants, cytokine serum levels/profiles, and disease severity in critically and noncritically ill COVID-19 patients. Methods: This cross-sectional study recruited 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 from six collection sites across the United Arab Emirates. Medical files were accessed to retrieve clinical data. Blood samples were collected from all participants. Patients were divided into two clinical groups, noncritical (n = 453) and critical (n = 193), according to World Health Organization classification guidelines for COVID-19 patients. Cytokine analyses were conducted on serum of a subset of the cohort, specifically on 426 participants (noncritical, 264; critical, 162). Candidate gene analyses of 33 cytokine-related genes (2,836 variants) were extracted from a genome-wide association study to identify genetic variants with pleiotropic effects on a specific cytokine and the severity of COVID-19 disease. Results: Age, body mass index (BMI), and pre-existing medical conditions were found to be significant risk factors that contribute to COVID-19 disease severity. After correcting for age, sex, and BMI, IP-10 ( P < 0.001), IFN ( P = 0.001), IL-6 ( P < 0.001), and CXCL-16 ( P < 0.001) serum levels were significantly higher among critical COVID-19 cases, when compared with noncritically ill patients. To investigate if the genetic variants involved in the serum cytokine levels are associated with COVID-19 severity, we studied several genes. Single nucleotide polymorphisms in IL6 (rs1554606; odd ratio (OR) G = 0.67 [0.66, 0.68]; P = 0.017), IFNG (rs2069718; OR G = 0.63 [0.62, 0.64]; P = 0.001), MIP (rs799187; OR A = 1.69 [1.66, 1.72]; P = 0.034), and CXCL16 (rs8071286; OR A = 1.42 [1.41, 1.44]; P = 0.018) were found to be associated with critically ill patients. Polymorphisms in the CXCL10 , CCL2 , IL1 , CCL7 , and TNF genes were not associated with the COVID-19 critical phenotype. The genotypes of IL-6 (gene, IL6 [7p15.3]) and CXCL-16 (gene, CXCL16 [17p13.2]) were significantly associated with the serum levels of the respective cytokine in critical cases of COVID-19. Conclusion: Data obtained from measuring cytokine levels and genetic variant analyses suggest that IL-6 and CXCL-16 could potentially be used as potential biomarkers for monitoring disease progression of COVID-19 patients. The findings in this study suggest that specific cytokine gene variants correlate with serum levels of the specific cytokine. These genetic variants could be of assistance in the early identification of high-risk patients on admission to the clinic to improve the management of COVID-19 patients and other infectious diseases.

A Pilot Study of Associations Between the Occurrence of Palpitations and Cytokine Gene Variations in Women Prior to Breast Cancer Surgery.

Palpitations are common and have a negative impact on women's quality of life. While evidence suggests that inflammatory mechanisms may play a role in the development of palpitations, no studies have evaluated for this association in patients with breast cancer who report palpitations prior to surgery. The purpose of this pilot study was to evaluate for associations between the occurrence of palpitations and single nucleotide polymorphisms (SNPs) in genes for pro- and anti-inflammatory cytokines, their receptors, and transcriptional regulators. Patients were recruited prior to surgery and completed a self-report questionnaire on the occurrence of palpitations. Genotyping of SNPs in cytokine genes was performed using a custom array. Multiple logistic regression analyses were done to identify associations between the occurrence of palpitations and SNPs in fifteen candidate genes. Of the 82 SNPs evaluated in the bivariate analyses, eleven SNPs in 6 genes were associated with the occurrence of palpitations. After controlling for functional status, the occurrence of back pain, and self-reported and genomic estimates of race/ethnicity, 3 SNPs in 3 different genes (i.e., interleukin (IL) 1-beta (IL1B) rs1143643, IL10 rs3024505, IL13 rs1295686) were associated with the occurrence of palpitations prior to surgery (all p ≤ .038). While these preliminary findings warrant replication, they suggest that inflammatory mechanisms may contribute to the subjective sensation of palpitations in women prior to breast cancer surgery.

Cytokine gene variants of TNF-α and IL-10 in the propensity of type 2 diabetes in south Indian population

Chronic inflammation plays an important role in type 2 diabetes mellitus (T2DM), a common endocrinological pro-inflammatory disorder associated with insulin resistance. The objective of the present study is to see individual and combined effect of TNF-α (rs361525, rs1800629) and IL-10 (rs1800872, rs1800896) genes on T2DM susceptibility The genotyping was carried out in 200 T2DM patients and 200 healthy controls by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) using suitable primers. The results shown that TNF-α (GA of rs361525 & rs1800629) and IL-10 (AA of rs1800872 & GA of rs1800896) genes are significantly linked with T2DM development. The presence of AA-GA genotype combination for both TNF-α and IL-10 genes were elevating the risk of T2DM. Moreover, individuals bearing haplotypes AAAA, AACA and AAAG experience the increased risk of T2DM. Furthermore, gene-gene interaction analysis shown that TNF-α (GA of rs361525 & rs1800896) gene redundantly confer 3.4-fold elevated risk for T2DM. In gene-environment interaction, GA of TNF-α −1800896, W/H ratio and TG/HDL ratio were redundantly interacted each other and increase the risk of T2DM by 67-times. In conclusion, our results reveal that there is a significant association between foresaid TNF-α, IL-10 gene promoter polymorphisms and T2DM development. To the best of our knowledge this study is the first of its kind in the literature reporting the epistatic association of TNF-α (rs1800629G/A) gene with TG/HDL ratio and W/H ratio over IL-10 gene polymorphisms for T2DM susceptibility among south Indians.

Cytokine gene polymorphism frequencies in Turkish population living in Marmara region

Abstract Objectives Sequence variants in cytokine genes are related to affect cytokine gene levels. In this study, it was aimed to examine eight single nucleotide polymorphisms (SNPs) in five cytokine genes (TNF-α, INF-γ, IL-6, IL10, TGF-β) for the Turkish population living in Marmara region and to reveal the genetic distance between the study group and other populations. Methods In this study, three-hundred unrelated healthy individuals were involved and all genotyping were performed by using sequence-specific primers PCR (PCR-SSP) method. The SNP data were analyzed for Hardy Weinberg equilibrium fit by calculating expected genotype frequencies and comparing them to the observed values using Arlequin software version 3.1. The genetic distances between the study group and other populations were calculated and a neighbor-joining tree was constructed by PHYLIP. Results The observed genotypes of TNF-α (−308), IFN-γ (+874), TGF-β (codon 10), and TGF-β (codon 25) of the subjects were found to be similar with other populations investigated in this study. However, there is a significant frequency difference for IL-6 and IL-10 genotypes between populations. Conclusions The current population study provided more reference values for these polymorphisms and generated a control group to be used in further association studies especially for transplantation, GVHD, autoimmune and malign disease.

COMPLEX ANALYSIS OF THE ROLE OF CYTOKINE GENE POLYMORPHISMS AS PROGNOSTIC FACTOR OF THE RISK OF PLASMA CELL MYELOMA IN PERSONS SUFFERED AFTER THE CHORNOBYL NPP ACCIDENT.

to provide a comparative characterization of the prevalence of polymorphic variants of cytokine genes in plasma cell myeloma (PCM) patients suffered after the Chornobyl disaster and patients who were in contact with ionizing radiation within the natural radiation background, based on comparison with population controls to determine their contribution as genetic markers of disease risk. Molecular genetic studies of polymorphism of cytokine genes (TNF-α, TGF-β1, IL-6, IL-10, IFN-γ) and complex frequency analysis of occurrence in three-, four-, and five-locus combinations of their allelic variants as prognostic markers of the risks of plasma cell myeloma was carried out in 102 patients - 56 victims of the Chornobyl nuclear power plant accident and 46 patients irradiated within the limits of the natural radiation background, in comparison with the control group (364 practically healthy people, residents of the Central geno-geographical region of Ukraine). The same probable increase in the prevalence of the TGF-β genotype codon10 T/T of the TGF-β1 gene was established in the groups of patients irradiated after the Chornobyl NPP accident and non-irradiated patients. In patients with plasma cell myeloma a protective effect for IL-10 -1082 A/G and an association with the risk of disease occurrence for IL-10 -1082 G/G were determined. Probable difference in the frequency of the TGF-β1 genotype codon10 T/T of the TGF-β1 gene in the observed groups relative to the control group provides grounds for considering this single-nucleotide polymorphism of the TGF-β1 gene as an immunogenetic factor of predisposition to the development of PCM independent of exogenous factors. The study of the contribution of multigene combinations of «gene-gene» interaction indicates their role in the mechanisms of plasma cell myeloma occurrence and confirms the presence of an additive interaction.

Cytokine gene variants and socio-demographic characteristics as predictors of cervical cancer: A machine learning approach

Cervical cancer is still one of the most prevalent cancers in women and a significant cause of mortality. Cytokine gene variants and socio-demographic characteristics have been reported as biomarkers for determining the cervical cancer risk in the Indian population. This study was designed to apply a machine learning-based model using these risk factors for better prognosis and prediction of cervical cancer. This study includes the dataset of cytokine gene variants, clinical and socio-demographic characteristics of normal healthy control subjects, and cervical cancer cases. Different risk factors, including demographic details and cytokine gene variants, were analysed using different machine learning approaches. Various statistical parameters were used for evaluating the proposed method. After multi-step data processing and random splitting of the dataset, machine learning methods were applied and evaluated with 5-fold cross-validation and also tested on the unseen data records of a collected dataset for proper evaluation and analysis. The proposed approaches were verified after analysing various performance metrics. The logistic regression technique achieved the highest average accuracy of 82.25% and the highest average F1-score of 82.58% among all the methods. Ridge classifiers and the Gaussian Naïve Bayes classifier achieved the highest sensitivity—85%. The ridge classifier surpasses most of the machine learning classifiers with 84.78% accuracy and 97.83% sensitivity. The risk factors analysed in this study can be taken as biomarkers in developing a cervical cancer diagnosis system. The outcomes demonstrate that the machine learning assisted analysis of cytokine gene variants and socio-demographic characteristics can be utilised effectively for predicting the risk of developing cervical cancer.

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.

Analysis of Interleukin-1 Receptor Antagonist Variable Number Tandem Repeat Variant in Recurrent Aphthous Stomatitis.

Recurrent aphthous stomatitis (RAS) is one of the common oral inflammatory diseases. As immunological and genetic factors have been held responsible for the pathogenesis of RAS, the objective of this study was to determine whether the interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) variant is a risk factor for the development of RAS in Turkish patients and to define its contribution to the increased risk. The IL-1Ra VNTR variant was evaluated in 169 RAS patients and 171 healthy controls by the polymerase chain reaction (PCR) method. No statistically significant difference was found in the genotype distributions and allele frequencies of IL-1Ra VNTR variant between RAS patients and healthy controls. Lack of association between IL-1Ra VNTR variant and RAS could indicate that IL-1Ra has no significant role in the pathophysiology of RAS. However, it still appears to be very worthwhile to continue to search for cytokine gene variants in order to predict the development of such disease.

Cytokine gene variants and treatment outcome of cisplatin-based concomitant chemoradiotherapy in cervical cancer

ABSTRACTBackground: Cervical cancer is the second most common cancer among women after breast cancer. Its standard treatment is cisplatin-based concomitant chemoradiotherapy. Chronic inflammation in uterine cervix triggers both pro- and anti-inflammatory pathways. The unpredictability in toxicity and efficacy of treatment is a major challenge. We hypothesized a link between IL-1, IL-6 and TNF gene variants and treatment response.Material & Methods: We genotyped 246 cervical cancer cases and 246 controls by PCR, PCR-RFLP and ARMS-PCR. Treatment and response were evaluated by RECIST criteria. Chemotherapy and radiation doses were same for all patients, whilst 48 were followed-up for 36 months after treatment.Results: SNPs in IL-1RN, IL-1β, IL-6 and TNFα were linked with cervical cancer. Cases with certain allele combinations in IL-1RN, IL-1β, IL-6(-597A/G) and TNF-α showed odds ratios (95% CI) of up to 17.54 (2.7–24.08) for the presence of cervical cancer. Variant IL-1β (-511T/C) was linked to vital status but none were linked to overall survival.Conclusion: Certain cytokine gene variants may help detect susceptibility to cervical cancer and predict response to chemoradiotherapy.

1620P - Cytokine genetic variations and worse quality of life among family caregivers of head and neck cancer patients in palliative care

BackgroundHigh inflammatory cytokine levels can lead to severe fatigue and alter the quality of life (QoL) of family caregivers (FCGs) of patients with head and neck cancer in palliative care (HNCPC). In addition, single nucleotide variants (SNVs) in cytokine genes, such as IL1B c-598T>C (rs16944), IL1R2 c.-2009G>A (rs4141134), IL6 c.-237G>C (rs1800795), and TREML2 c.430A>G (rs3747742), can influence individual differences in cytokine production. However, the roles of the referred SNVs on the QoL of FCGs are unknown. Thus, the aim of our study was to evaluate the influence of the referred SNVs in the QoL of FCGs of patients with HNCPC. MethodsGenomic DNA of 100 FCGs of patients with HNCPC was analyzed by real-time PCR to identify the genotypes. QoL was measured with the abbreviated World Health Organization QoL questionnaire (WHOQOL-bref). The cut-off of the score was lower than 60 for worse QoL. Differences between groups were assessed by Fisher’s exact test, chi-square (bivariate analysis), and multiple linear regression. ResultsFCGs who carried IL6 GG (62.8% vs. 49.2%, odds ratio [OR]: 2.78, 95% confidence interval [CI]: 1.03-7.44, p=0.04) and TREML2 AA (60.0% vs. 44.6%, OR: 2.68, 95% CI: 1.03-7.01, p=0.04) had worse QoL for the overall QoL domain than non-carriers. The frequency of the genotype TREML2 AA was higher in FCGs with lower score for physical domain (61.0% vs. 42.4%, OR: 2.69, 95% CI: 1.05-6.87, p=0.03). FCGs who carried IL1B TT genotype had worse QoL for the social domain than others (48.9% vs. 32.1%, OR: 3.49, 95% CI: 1.03-7.01, p=0.01). ConclusionsGenotypes of the IL1B, IL6, and TREML genes, associated with higher inflammatory levels, seem to influence the QoL of FCGs. We believe that our results can contribute to identify FCGs with worse QoL for physical, psychological, and social aspects and provide better and more specialized care. Legal entity responsible for the studyThe authors. FundingFAPESP. DisclosureAll authors have declared no conflicts of interest.

Polymorphisms of Cytokine Genes in Genital Endometriosis

Links between polymorphisms in cytokine genes and the development of genital endometriosis (GE) in women of reproductive age, its clinical manifestations, stages of progression, and efficacy of combined treatment were analyzed. Polymorphic variants of cytokine genes were identified by analysis of restriction fragment length polymorphisms (RFLP). Carriership of not only individual cytokine gene polymorphisms, i.e., the C-511T polymorphism of the IL1B gene (T allele), the T-330G polymorphism of the IL2 gene (G allele), the C-590T polymorphism of the IL4 gene (T allele), the G-174C polymorphism of the IL6 gene (C allele), the C-592A polymorphism of the IL10 gene (A allele and CA and AA genotypes), the G-308A polymorphism of the TNFA gene (A allele and AA genotype), and the C-590T polymorphism of the TGFB (T allele and CT genotype) gene, but also their combination, i.e., IL2GG/IL4CC/IL10CC/TNFAGG, was found to predispose to the development of GE. Carriership of the TT genotype of the IL1B C-511T polymorphism was found to predispose to the development of pelvic pain in GE and GE stages III–IV. Infertility in GE and the efficacy of its hormonal therapy were associated with carriership not of individual cytokine gene polymorphisms but with their combinations – IL2TT/IL4CC/IL10CC/TNFAGG and IL1CT/IL4CC/IL6GG/ IL10CC/TGFBCC, respectively.