Abstract
BackgroundSome 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.MethodsReported 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.ResultsHardy 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.
Highlights
Human cytomegalovirus (HCMV) causes the most common intrauterine infections, affecting approximately 40% to 100% of pregnant women [1,2,3,4,5]
Hardy Weinberg equilibrium was observed for almost all single nucleotide polymorphisms (SNP), both infected and non-infected patients, with exception of TLR4 896 A>G polymorphism in the control group (P0.050)
The CC genotype at TLR4 1196 SNP and the GA variant at TLR9 2848 G>A SNP were significantly associated with HCMV infection (P0.050)
Summary
Human cytomegalovirus (HCMV) causes the most common intrauterine infections, affecting approximately 40% to 100% of pregnant women [1,2,3,4,5]. Regarding the non-specific immunity to HCMV infection, a crucial role was assigned to Toll-like receptors (TLRs) [13,14,15,16]. The expression of genes, encoding TLR2 and endosomal TLR3 and TLR9 molecules, as well as scavenger receptor A type 1 (SR-A1), tyrosine-protein kinase Lyn, IL-12 p35 subunit, TIR domain containing adaptor-inducing interferon-beta (TRIF), interferon regulatory factor 3 (IRF-3) and interferon beta (IFN-ß) were observed to be induced after infection of human acute monocytic leukemia cell line THP1 and foreskin fibroblast cell lines with HCMV [17, 18]. TLR9 expression was strongly induced in the primary fibroblasts, infected with HCMV [14, 17]. 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
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