Genetic Polymorphisms in Toll-Like Receptors among Pediatric Patients with Renal Parenchymal Infections of Different Clinical Severities

Abstract

BackgroundAlthough several studies have suggested single gene defects or variations in the genes associated with host immune response could confer differences in susceptibility to urinary pathogen invasion, no studies have examined the genetic polymorphisms in various toll-like receptors (TLRs) that activate innate immune responses in pediatric renal parenchymal infections of different clinical severities, namely acute pyelonephritis and the clinically more severe disease, acute lobar nephronia.MethodologyPatients who fulfilled the diagnostic criteria for acute pyelonephritis (APN) and acute lobar nephronia (ALN) without underlying diseases or structural anomalies, except for vesicoureteral reflux (VUR), were enrolled. Genotyping of the single nucleotide polymorphisms (SNPs) in the genes encoding TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6 was performed by matrix-assisted laser desorption/ionization time-of-flight-based mini-sequencing analysis.Principal FindingsA total of 16 SNPs were selected for genotyping. Analysis of 96 normal and 48 patients’ samples revealed that only four SNPs had heterozygosity rates >0.01. These SNPs were selected for further investigation. Hardy-Weinberg equilibrium was satisfied for the observed genotype frequencies. Statistically significant differences in the genotype frequency of TLR-2 (rs3804100, T1350C) between controls and ALN or (APN+ALN) combined group were identified using the recessive model with the correction for multiple-SNP testing. Further genotype pattern frequency analysis in TLR-2 SNPs (rs3804099 and rs3804100) showed significantly reduced occurrence of the rare allele homozygote (CC+CC) in the no-VUR subgroup of APN and ALN cases.ConclusionsAs the inflammatory responses in ALN patients are more severe than those in APN patients (higher CRP levels, longer duration of fever after antibiotic treatment), these findings suggest that the genetic variant in TLR-2 (rs3804100, T1350C) may protect the host from severe urinary tract infections as ALN.

Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation

“…In line with our study, Cheng et al . did not find an association of the minor allele of TLR5 variant p.Arg392Ter with native kidney diseases [ 57 ]. The residual TLR variants, which includes TLR8 p.Met1Val that showed an association with end-stage renal disease in our cohort, have not been described before.…”

Genetic Polymorphisms in Inflammasome-Dependent Innate Immunity among Pediatric Patients with Severe Renal Parenchymal Infections

“…This study is part of our ongoing investigation of the pathogenic host and bacterial urovirulence factors related to pediatric APN and ALN [ 5 , 14 , 15 ]. Patients were enrolled in the study if they fulfilled the diagnostic criteria for APN and ALN caused by E .…”

“…Despite of inflammasome-dependent immune response has been reported to be associated with various microbial sensing and reaction to microbial infections [ 13 , 16 , 21 , 22 ], none has explored its likely association with urinary tract infections, to our knowledge. Henceforth, to exam inflammasome-dependent innate immunity pathway on pediatric patients with severe renal parenchymal infections might provide supplementary information to our earlier findings based on the TLR-dependent pathway [ 14 , 15 ]. In this investigation, we attempted to assess the likely variations in genes associated with the inflammasome-dependent innate immunity pathway for pediatric patients with various severe UTIs.…”

“…We demonstrated that the AA genotype and A allele of the IL–8 SNP were related to patient susceptibility to parenchymal infection and were correlated with the severity of infection in pediatric patients with APN and ALN, probably due to the upregulation of IL–8 expression [ 14 ]. Additionally, MALDI-TOF SNP analyses revealed that the genetic variant in TLR–2 (rs3804100, T1350C) might protect the host from severe UTIs such as ALN [ 15 ].…”

“…This investigation was part of our ongoing effort to explore the pathogenic host and bacterial urovirulence factors related to pediatric APN and ALN; as such, it includes patients continuously enrolled since our previous studies [ 5 , 14 , 15 ]. Therefore, compared with our previous reports, this study enrolled a greater number of participants, with a total of 138 APN and 222 ALN cases and 225 controls, including those cases in our earlier investigations on SNPs in TLR-dependent innate immunity pathway genes (113 APN and 172 ALN cases and 222 controls) [ 14 , 15 ]. Genotying for the genes associated with the inflammsome-dependent pathway was commenced on the second half of year 2012, while genotyping for genes associated with the TLR-dependent pathway presented in earlier publications [ 14 , 15 ] has been completed in 2010.…”