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Background/aim: This research was aimed to evaluate the association between three selected single nucleotide polymorphisms (SNPs) within the CDKN2A (P14ARF) tumour suppressor gene and the incidence of endometrial cancer (EC) in postmenopausal women., Patients and Methods: The study included 194 postmenopausal women; 144 with EC and 50 non-cancer controls. Genotypes in P14ARF rs3088440, rs3731217 and rs3731245 polymorphisms were assayed using PCR-RFLP and confirmed by sequencing., Results: Regarding the rs3088440 polymorphism, CT, and CT-TT genotypes, were more prevalent among EC patients than in controls (OR=5.55, p=0.023, OR=5.29, p=0.027; and OR=2.92, p=0.023, respectively). The T allele within rs3088440 was more prevalent in EC females than in controls (χ 2 =4.7, p=0.030). Considering rs3731217, TG and TG-GG genotypes were less prevalent among EC (OR=0.34, p=0.024 or p=0.023; and OR=0.38, p=0.035, respectively)., Conclusion: Polymorphisms in the CDKN2A gene are associated with EC in postmenopausal women., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The aim of this study was to determine the joint effect of single nucleotide polymorphisms (SNPs) of MDM2, TP53, and CDKN2A (P14ARF) genes on the onset and course of endometrial cancer (EC) in postmenopausal women., Materials and Methods: The study group consisted of 144 EC women and 50 non-cancer controls. MDM2 rs22279744, TP53 rs1042522, and P14ARF rs3088440, rs3731217, and rs3731245 SNPs were analysed., Results: The double-SNP combinations T-C, T-T, or T-G in MDM2 SNP 309 and P14ARF polymorphisms decreased EC risk. The triple-SNP combinations T-C-T, T-C-G, or T-T-G in MDM2 SNP and two P14ARF polymorphisms decreased EC risk. The multiple-SNP combination T-C-T-G in MDM2 and three P14ARF polymorphisms decreased EC risk. The G-Arg-C-T-G carriers were at increased EC risk, while the T-Arg-C-T-G carriers were at decreased EC risk., Conclusion: MDM2 SNP309 plays a role in EC onset in postmenopausal women., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Toxoplasma gondii causes one of the most common intrauterine infections worldwide, thus being a severe threat during pregnancy. IL1, IL6, IL10, IL12, and TNF-α cytokines were reported to be involved in immune responses to infections with T. gondii. The research was aimed to reveal relationships between genetic changes within the polymorphisms of these cytokine genes and the incidence of T. gondii infection among pregnant women, as well as congenital transmission of the parasite to the foetuses of their infected mothers., Methods: The primary study was performed in 148 Polish pregnant women, including 74 T. gondii-infected patients and 74 age-matched uninfected individuals; and further analysis - among the additional 142 pregnant women. Genotypes within IL1A -889 C>T, IL1B +3954 C>T, IL6 -174 G>C, IL10 -1082 G>A, IL12B -1188 A>C and TNFA -308 G>A single nucleotide polymorphisms (SNPs) were determined, using self-designed nested PCR-RFLP assays. Randomly selected PCR products, representing distinct genotypes in the analyzed polymorphisms, were confirmed by sequencing, using the Sanger method. A statistical analysis was carried out of relationships between genetic alterations within studied SNPs and the occurrence of T. gondii infection, using the following tools: cross-tabulation, Pearson's Chi-square test and the logistic regression model to estimate genetic models of inheritance. A power analysis of statistically significant outcomes was performed by Cramér's V test., Results: A multiple-SNP analysis showed TC haplotype for IL1A and IL1B SNPs to be significantly associated with a decreased risk of the parasitic infection (OR 0.41, P≤0.050). The association remained important after power analysis (Cramér's V = 0.39, χ 2  = 7.73, P≤0.050), and the additional analysis with larger groups of patients (OR 0.47, P≤0.050). Moreover, the CCCAGA complex variants were for all the studied polymorphisms at an increased risk of T. gondii infection (OR 8.14, P≤0.050), although this strong relationship was not significant in the further analysis (Cramér's V = 0.76, χ 2  = 26.81, P = 0.310). Regarding the susceptibility to congenital transmission of T. gondii from mothers to their foetuses among the infected pregnant women, the presence of GA heterozygotic status within IL10 polymorphism significantly increased the risk of parasitic transmission (OR 5.73 in the codominant model and OR 5.18 in the overdominant model; P≤0.050). The correlation stayed important in the power analysis (Cramér's V = 0.29, χ 2  = 6.03, P≤0.050), although it was non-significant in larger groups of patients. Important relationships specific for the first study cohort remained non-significant in the second group of studied pregnant women., Conclusions: Within the analyzed cohort of Polish pregnant women, the genetic modifications from SNPs of genes, encoding both the proinflammatory IL1α, IL1β, IL6, IL12 and TNF-α, and anti-inflammatory IL10 cytokines, may have been associated with susceptibility to T. gondii infection. It is the first study on the contribution of cytokine genes polymorphisms to the occurrence of T. gondii infection during pregnancy. Further studies for other populations of pregnant women would be justified to reveal a detailed role of the analyzed polymorphisms for the occurrence of T. gondii infections during pregnancy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: The research was conducted to evaluate the role of genotypes, haplotypes and multiple-SNP variants in the range of TLR2, TLR4 and TLR9 single nucleotide polymorphisms (SNPs) in the development of Toxoplasma gondii infection among Polish pregnant women., Material and Methods: The study was performed for 116 Polish pregnant women, including 51 patients infected with T. gondii, and 65 age-matched control pregnant individuals. Genotypes in TLR2 2258 G>A, TLR4 896 A>G, TLR4 1196 C>T and TLR9 2848 G>A SNPs were estimated by self-designed, nested PCR-RFLP assays. Randomly selected PCR products, representative for distinct genotypes in the studied polymorphisms, were confirmed by sequencing. All the genotypes were calculated for Hardy-Weinberg (H-W) equilibrium and TLR4 variants were tested for linkage disequilibrium. Relationships were assessed between alleles, genotypes, haplotypes or multiple-SNP variants in TLR polymorphisms and the occurrence of T. gondii infection in pregnant women, using a logistic regression model., Results: All the analyzed genotypes preserved the H-W equilibrium among the studied groups of patients (P>0.050). Similar distribution of distinct alleles and individual genotypes in TLR SNPs, as well as of haplotypes in TLR4 polymorphisms, were observed in T. gondii infected and control uninfected pregnant women. However, the GACG multiple-SNP variant, within the range of all the four studied polymorphisms, was correlated with a decreased risk of the parasitic infection (OR 0.52, 95% CI 0.28-0.97; P≤0.050)., Conclusions: The polymorphisms, located within TLR2, TLR4 and TLR9 genes, may be involved together in occurrence of T. gondii infection among Polish pregnant women., (Copyright © 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Purpose: The research project targeted the distribution of genotypes, alleles and haplotypes in single nucleotide polymorphisms (SNPs) within the interleukin (IL) 1A, IL1B, IL6, IL12B and TNFA genes, in fetuses and neonates, congenitally infected with human cytomegalovirus (HCMV), and among uninfected controls., Methods: The study included 20 fetuses and neonates with congenital HCMV infection and 31 control individuals. The genotypes in SNPs of the studied cytokine genes were identified by a self-designed nested PCR-RFLP assays. Selected genotypes, representing distinct variants in analyzed polymorphisms, were confirmed by sequencing. The relationship between the genetic status of the studied polymorphisms and congenital infection development was estimated, using a logistic regression model., Results: The CT haplotype, composed of C allele determined in IL1A -889 C > T and T allele in IL1B +3954 C > T SNP, increased the risk of congenital HCMV infection, as well as the onset of disease related symptoms (P ≤ 0.0001). Considering disease outcome, the risk of development of symptoms, was increased among the CT heterozygotes in IL1A -889 C > T polymorphism (OR 2.86, 95% CI 0.24-33.90; P = 0.045). Moreover, multiple-SNP variants CCGAG in the range of all the SNPs, analyzed in the study, increased the risk of congenital infection with HCMV (OR 7.94, 95% CI 1.38-45.69; P = 0.026)., Conclusions: Polymorphisms within the proinflammatory cytokine genes may contribute to the development of congenital infection with HCMV., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Human cytomegalovirus (HCMV) is the most common cause of intrauterine infections worldwide. The toll-like receptors (TLRs) have been reported as important factors in immune response against HCMV. Particularly, TLR2, TLR4 and TLR9 have been shown to be involved in antiviral immunity. Evaluation of the role of single nucleotide polymorphisms (SNPs), located within TLR2, TLR4 and TLR9 genes, in the development of human cytomegalovirus (HCMV) infection in pregnant women and their fetuses and neonates, was performed., Methods: The study was performed for 131 pregnant women, including 66 patients infected with HCMV during pregnancy, and 65 age-matched control pregnant individuals. The patients were selected to the study, based on serological status of anti-HCMV IgG and IgM antibodies and on the presence of viral DNA in their body fluids. Genotypes in TLR2 2258 A > G, TLR4 896 G > A and 1196 C > T and TLR9 2848 G > A SNPs were determined by self-designed nested PCR-RFLP assays. Randomly selected PCR products, representative for distinct genotypes in TLR SNPs, were confirmed by sequencing. A relationship between the genotypes, alleles, haplotypes and multiple variants in the studied polymorphisms, and the occurrence of HCMV infection in pregnant women and their offsprings, was determined, using a logistic regression model., Results: Genotypes in all the analyzed polymorphisms preserved the Hardy-Weinberg equilibrium in pregnant women, both infected and uninfected with HCMV (P > 0.050). GG homozygotic and GA heterozygotic status in TLR9 2848 G > A SNP decreased significantly the occurrence of HCMV infection (OR 0.44 95% CI 0.21-0.94 in the dominant model, P ≤ 0.050). The G allele in TLR9 SNP was significantly more frequent among the uninfected pregnant women than among the infected ones (χ 2  = 4.14, P ≤ 0.050). Considering other polymorphisms, similar frequencies of distinct genotypes, haplotypes and multiple-SNP variants were observed between the studied groups of patients., Conclusions: TLR9 2848 G > A SNP may be associated with HCMV infection in pregnant women.

Background: Human cytomegalovirus (HCMV) is responsible for the most common intrauterine infections, which may be acquired congenitally from infected pregnant woman to fetus. The research was aimed to estimate the role of three single nucleotide polymorphisms (SNPs) located in TLR2 gene, and the common contribution of TLR2, and previously studied TLR4 and TLR9 SNPs, to the occurrence of congenital HCMV infection in fetuses and newborns., Methods: The study was performed in 20 Polish fetuses and newborns, congenitally infected with HCMV, and in 31 uninfected controls, as well as with participation of pregnant women, the mothers of 16 infected and 14 uninfected offsprings. Genotypes in TLR2 SNPs were determined, using self-designed nested PCR-RFLP assays, and confirmed by sequencing. The genotypes were tested for Hardy-Weinberg (H-W) equilibrium, and for their relationship with the development of congenital cytomegaly, using a logistic regression model. The common influence of TLR2, TLR4 and TLR9 SNPs on the occurrence of congenital disease was estimated by multiple-SNP analysis., Results: Distribution of the genotypes and alleles in TLR2 1350 T>C and 2029 C>T SNPs was similar between the studied groups of fetuses and neonates. In case of 2258 G>A polymorphism, the GA heterozygotic status was significantly more frequent in the infected cases than among the uninfected individuals (25.0% vs. 3.2%, respectively), and increased the risk of HCMV infection (OR 10.00, 95% CI 1.07-93.44; P ≤ 0.050). Similarly, the A allele within 2258 G>A polymorphism was significantly more frequent among the infected offsprings than in the uninfected ones (12.5% vs. 1.6%; P ≤ 0.050). Complex AA variants for both TLR2 2258 and TLR9 2848 G>A polymorphisms, were estimated to be at increased risk of congenital HCMV infection (OR 11.58, 95% CI 1.19-112.59; P ≤ 0.050). Additionally, significant relationships were observed between the occurrence of complex AA or GA variants for both TLR2 and TLR9 SNPs and the increased viral loads, determined in fetal amniotic fluids and in maternal blood or urine specimens (P ≤ 0.050)., Conclusions: Among various TLR2, TLR4 and TLR9 polymorphisms, TLR2 2258 G>A SNP seems to be an important factor associated with increased risk of congenital HCMV infection in Polish fetuses and neonates.

Background: Some single nucleotide polymorphisms (SNP), located in Toll-like receptor (TLR) genes, were reported to be associated with human cytomegalovirus (HCMV) infections. The study was aimed to assess the correlation of SNPs at TLR4 and TLR9 genes with the occurrence of congenital cytomegaly, based on available samples., Methods: Reported case-control study included both HCMV infected and non-infected fetuses and newborns. The specimens were classified to the molecular analyses, based on serological features of the recent infection and HCMV DNAemia in body fluids. TLR SNPs were studied, using multiplex nested PCR-RFLP assay, and determined genotypes were confirmed by sequencing. Hardy-Weinberg equilibrium was assessed for the identified genotypes. The linkage disequilibrium was also estimated for TLR4 SNPs. A relationship between the status of TLR genotypes and congenital cytomegaly development was estimated, using a logistic regression model., Results: Hardy Weinberg equilibrium was observed for almost all SNPs, both infected and non-infected patients, with exception of TLR4 896 A>G polymorphism in the control group (P≤0.050). TLR4 896 A>G and 1196 C>T SNPs were found in linkage disequilibrium in both study groups (P≤0.050). The CC genotype at TLR4 1196 SNP and the GA variant at TLR9 2848 G>A SNP were significantly associated with HCMV infection (P≤0.050). The risk of congenital cytomegaly was higher in heterozygotes at TLR9 SNP than in the carriers of other genotypic variants at the reported locus (OR 4.81; P≤0.050). The GC haplotype at TLR4 SNPs and GCA variants at TLR4 and TLR9 SNPs were significantly associated with HCMV infection (P≤0.0001). The ACA variants were more frequent among fetuses and neonates with symptomatic, rather than asymptomatic cytomegaly (P≤0.0001)., Conclusions: TLR4 and TLR9 polymorphisms may contribute to the development of congenital infection with HCMV in fetuses and neonates. The TLR9 2848 GA heterozygotic status possibly predisposes to HCMV infection, increasing the risk of congenital cytomegaly development.

Toll-like receptors (TLRs) play a crucial role in non-specific immunity against various infections. The most common intrauterine infection, caused by Human cytomegalovirus (HCMV), results in perinatal morbidity and mortality of primary infected fetuses. The induction of immune response by TLRs was observed in HCMV infections in murine models and cell lines cultured in vitro. Studies reported an immunological response in pregnant women with primary HCMV infection and TLR2 activity in collecting of HCMV particles in placental syncytiotrophoblasts (STs) in vivo and cultured ST, and in stimulation of tumor necrosis factor (TNF)-α expression and damage of villous trophoblast. Expression levels of TLRs are associated with cell type, stage of pregnancy and response to microorganisms. We show the effect of HCMV infection on the development of pregnancy as well as the effect of TLR single-nucleotide polymorphisms on the occurrence and course of infectious diseases, immune response and diseases of pregnancy. We report the impact of TLRs on the function of miRNAs and the altered expression levels of these molecules, as observed in HCMV infections. We suggest that the methylation status of TLR gene promoter regions as epigenetic modifications may be significant in the immune response to HCMV infections. We conclude that it is important to study in detail the molecular mechanisms of TLR function in the immune response to HCMV infections in pregnancy., (© 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)