title: Genetic Polymorphisms in Inflammasome-Dependent Innate Immunity among Pediatric Patients with Severe Renal Parenchymal Infections.
abstract: BACKGROUND
  Inflammasome innate immune response activation has been demonstrated in various inflammatory diseases and microbial infections. However, to our knowledge, no study has examined the inflammasome-dependent pathways in patients with urinary tract infection. Defective or variant genes associated with innate immunity are believed to alter the host's susceptibility to microbial infection. This study investigated genetic polymorphisms in genes encoding inflammasomes and the subsequent released cytokines in pediatric patients with severe renal parenchymal infections.
  
  
  METHODS
  This study included patients diagnosed with acute pyelonephritis (APN) and acute lobar nephronia (ALN) who had no underlying disease or structural anomalies other than vesicoureteral reflux (VUR). Single nucleotide polymorphism (SNP) genotyping was performed in the genes associated with inflammasome formation and activation (NLRP3, CARD8) and subsequent IL-1β cytokine generation (IL-1β).
  
  
  RESULTS
  A total of 40 SNPs were selected for initial genotyping. Analysis of samples from 48 patients each and 96 controls revealed that only nine SNPs (five SNPs in NLRP3; three SNPs in CARD8; one SNP in IL-1β) had heterozygosity rates >0.01. Hardy-Weinberg equilibrium was satisfied for the observed genotype frequencies of these SNPs. Analysis excluding patients with VUR, a well-known risk factor for severe UTIs, revealed a lower frequency of the CC genotype in NLRP3 (rs4612666) in patients with APN and ALN than in controls. Correction for multiple-SNP testing showed that the non-VUR subgroup of the APN+ALN combined patient groups remained significantly different from the control group (P < 0.0055).
  
  
  CONCLUSIONS
  This study is the first to suggest that the inflammasome-dependent innate immunity pathway is associated with the pathogenesis of pediatric severe renal parenchymal infections. Further investigation is warranted to clarify its pathogenic mechanism.
authors.affiliation: Division of Pediatric Nephrology, Department of Pediatrics, Chang Gung Children's Hospital, Chang Gung Memorial Hospital, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chi-Hui
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan; Department of Biotechnology, Ming-Chuan University, Taoyuan, Taiwan.
authors.forename: Yun-Shien
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Statistical Center for Clinical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Chee-Jen
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Institute of Oral Medicine, Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jui-Che
authors.initials: JC
authors.lastname: Lin
authors.affiliation: College of Medicine, Chang Gung University, Taoyuan, Taiwan; Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children's Hospital, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Tzou-Yien
authors.initials: TY
authors.lastname: Lin
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D007223:Infant; D058847:Inflammasomes / Q000235:genetics* / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011704:Pyelonephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology
chemical_list: D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009363:Neoplasm Proteins