TLR2 2258 G>A single nucleotide polymorphism and the risk of congenital infection with human cytomegalovirus

Wioletta Wujcicka,Mirosława Studzińska,Jan Wilczyński,Edyta Paradowska,Dorota Nowakowska

doi:10.1186/s12985-016-0679-z

Abstract

BackgroundHuman 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.MethodsThe 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.ResultsDistribution 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).ConclusionsAmong 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.

Highlights

Human cytomegalovirus (HCMV) is responsible for the most common intrauterine infections, which may be acquired congenitally from infected pregnant woman to fetus
The results of our study demonstrate that Toll-like receptor 2 (TLR2) 2258 G>A Single nucleotide polymorphism (SNP) may be an important genetic factor of the previously analyzed TLR2, TLR4 and TLR9 polymorphisms, which is involved in the development of congenital HCMV infection in Polish fetuses and neonates
The GA heterozygotic status in the polymorphic region was correlated with HCMV infection, increasing 10 times the risk of the infection and the A allele in TLR2 SNP was significantly more frequently found among the infected fetuses and neonates than in the uninfected controls

Summary

Introduction

Human cytomegalovirus (HCMV) is responsible for the most common intrauterine infections, which may be acquired congenitally from infected pregnant woman to fetus. Severe symptoms, diagnosed in about 10 to 15% of congenitally infected neonates, include microcephaly, ventriculomegaly, increased periventricular echogenicity and calcifications [6, 9, 12]. Other symptoms, such as hearing impairment, visual impairment or blindness, difficulties in learning and dyspraxia, observed during the first months or in the first few years of life, were determined in symptomatic congenital cytomegaly, they may occur in a condition, classified as asymptomatic at birth [1, 6, 9]

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