TLR9 2848 GA Heterozygotic Status Possibly Predisposes Fetuses and Newborns to Congenital Infection with Human Cytomegalovirus

Wujcicka, Wioletta; Paradowska, Edyta; Studzińska, Mirosława; Gaj, Zuzanna; Wilczyński, J; Leśnikowski, Zbigniew J.; Nowakowska, Dorota

doi:10.1371/journal.pone.0122831

Cited by 28 publications

(50 citation statements)

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“…Associations between TLR2 [16, 17], TLR4 [18], and TLR9 polymorphisms [19–22] with HCMV infection have been found. It was previously demonstrated that the TLR9 –1486 and 2848 polymorphisms as well as the TLR2 1350 SNP are associated with an enhanced risk of HCMV infection and disease in newborns and infants [23–25]. However, little is known about the role of TLR3 and TLR7 polymorphisms in the pathogenesis of cytomegaly.…”

Section: Introductionmentioning

confidence: 99%

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

et al. 2017

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Intracellular Toll-like receptor 3 (TLR3) recognizes viral double-stranded RNA (dsRNA) and activates antiviral immune responses through the production of type I interferons (IFNs) and inflammatory cytokines. This receptor binds to dsRNA molecules produced during human cytomegalovirus (HCMV) replication. TLR7 senses viral single-stranded RNA (ssRNA) in endosomes, and it can interact with endogenous RNAs. We determined the genotype distribution of single-nucleotide polymorphisms (SNPs) within the TLR3 and TLR7 genes in children with HCMV infection and the relationship between TLR polymorphisms and viral infection. We genotyped 59 children with symptomatic HCMV infection and 78 healthy individuals for SNPs in the TLR3 (rs3775290, c.1377C>T, F459F; rs3775291, c.1234C>T, L412F; rs3775296, c.-7C>A) and TLR7 (rs179008, c.32A>T, Q11L; rs5741880, c.3+1716G>T) genes. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and capillary electrophoresis. The HCMV DNA load was quantified by real-time PCR. We found an increased frequency of the heterozygous genotype TLR3 L412F in children with HCMV infection compared with uninfected cases. In individuals with a mutation present in at least one allele of the L412F SNP, an increased risk of HCMV disease was found, and this result remained highly significant after Bonferroni’s correction for multiple testing (Pc < 0.001). The heterozygous genotype of this SNP was associated with the increased risk of HCMV disease in an adjusted model that included the HCMV DNA copy number in whole blood and urine (P < 0.001 and P = 0.008, respectively). Moreover, those with a heterozygous genotype of rs3775296 showed an increased relative risk of HCMV infection (P = 0.042), but this association did not reach statistical significance after correction for multiple testing. In contrast, the rs3775290 SNP of TLR3 and TLR7 SNPs were not related to viral infection. A moderate linkage disequilibrium (LD) was observed between the SNPs rs3775291 and rs3775296 (r2 = 0.514). We suggest that the L412F polymorphism in the TLR3 gene could be a genetic risk factor for the development of HCMV disease.

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Section: Introductionmentioning

confidence: 99%

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

et al. 2017

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“…Therefore, the analyzed polymorphism was suggested to participate in the development of HCMV disease in humans [23]. Other studies also showed the SNPs located in TLR2 , as well as in TLR3 , TLR4 , TLR7 and TLR9 genes, to be contributing to HCMV infection [13, 14, 27]. So far, no study has shown any relationship between genetic alterations in TLR2 2258 G>A SNP and congenital HCMV infection.…”

Section: Introductionmentioning

confidence: 99%

“…We previously reported a possible contribution of TLR4 and TLR9 SNPs to congenital cytomegaly [14]. These recently published outcomes, as well as the available literature data on the contribution of TLR2 SNPs to the occurrence of HCMV infection, prompted us to undertake further research, evaluating the role of TLR2 1350 T>C coding synonymous (Ser450, rs3804100), as well as 2029 C>T (Arg677Trp, rs121917864) and 2258 G>A non-synonymous (Arg753Gln) SNPs in the development of HCMV congenital infection in fetuses and neonates.…”

Section: Introductionmentioning

confidence: 99%

“…These recently published outcomes, as well as the available literature data on the contribution of TLR2 SNPs to the occurrence of HCMV infection, prompted us to undertake further research, evaluating the role of TLR2 1350 T>C coding synonymous (Ser450, rs3804100), as well as 2029 C>T (Arg677Trp, rs121917864) and 2258 G>A non-synonymous (Arg753Gln) SNPs in the development of HCMV congenital infection in fetuses and neonates. Moreover, the common influence of TLR2 2258 G>A, as well as of the recently studied TLR4 896 A>G, 1196 C>T and TLR9 2848 G>A SNPs [14] on the occurrence of the infection and on congenital cytomegaly development was also estimated. The distribution of genotypes and alleles in TLR4 and TLR9 polymorphisms, and of the haplotypes for TLR4 SNPs, between the analyzed groups of the offsprings, was reported in our previous paper [14].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the common influence of TLR2 2258 G>A, as well as of the recently studied TLR4 896 A>G, 1196 C>T and TLR9 2848 G>A SNPs [14] on the occurrence of the infection and on congenital cytomegaly development was also estimated. The distribution of genotypes and alleles in TLR4 and TLR9 polymorphisms, and of the haplotypes for TLR4 SNPs, between the analyzed groups of the offsprings, was reported in our previous paper [14]. …”

Section: Introductionmentioning

confidence: 99%

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

Wujcicka

Paradowska

Studzińska

et al. 2017

Virol J

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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.

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Possible role of TLR4 and TLR9 SNPs in protection against congenital toxoplasmosis

Wujcicka

Gaj

Wilczyński

et al. 2015

Eur J Clin Microbiol Infect Dis

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The purpose of this investigation was the determination of the distribution of genotypes at single nucleotide polymorphisms (SNPs) of the toll-like receptor 4 (TLR4) and the toll-like receptor 9 (TLR9) in fetuses and newborns congenitally infected with Toxoplasma gondii and the identification of genetic changes predisposing to infection development. The study involved 20 fetuses and newborns with congenital toxoplasmosis and 50 uninfected controls. The levels of IgG and IgM antibodies against T. gondii, as well as IgG avidity, were estimated by enzyme-linked fluorescent assay (ELFA) tests. T. gondii DNA loads in amniotic fluids were assayed by the real-time (RT) quantitative polymerase chain reaction (Q PCR) technique for parasitic B1 gene. TLR4 and TLR9 SNPs were identified using a self-designed multiplex nested PCR-restriction fragment length polymorphism (RFLP) assay. Randomly selected genotypes at SNPs were confirmed by sequencing. All the genotypes were tested for Hardy–Weinberg equilibrium and TLR4 genotypes were analyzed for linkage disequilibrium. A correlation was studied between the genotypes or haplotypes and the development of congenital toxoplasmosis using a logistic regression model. Single SNP analysis showed no statistically significant differences in the distribution of distinct genotypes at the analyzed TLR4 and TLR9 SNPs between T. gondii-infected fetuses and newborns and the controls. Taking into account the prevalence of alleles residing within polymorphic sites, similar prevalence rates were observed in both of the studied groups. The multiple SNP analysis indicated GTG variants at the TLR4 and TLR9 SNPs to be significantly less frequent in offspring with congenital toxoplasmosis than in uninfected offspring (p ≤ 0.0001). TLR4 and TLR9 SNPs seem to be involved in protection against congenital toxoplasmosis.

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TLR9 2848 GA Heterozygotic Status Possibly Predisposes Fetuses and Newborns to Congenital Infection with Human Cytomegalovirus

Cited by 28 publications

References 46 publications

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

Association of TLR3 L412F Polymorphism with Cytomegalovirus Infection in Children

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

Possible role of TLR4 and TLR9 SNPs in protection against congenital toxoplasmosis

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