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Polymorphisms in ?-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux.

ABSTRACT: The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the ?-defensins, encoded by DEFA1A3, is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real-time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Study and 295 controls, and we correlated copy numbers with outcomes. Outcomes studied included reflux grade, UTIs during the study on placebo or antibiotics, bowel and bladder dysfunction, and renal scarring. Overall, 29% of patients and 16% of controls had less than or equal to five copies of DEFA1A3 (odds ratio, 2.09; 95% confidence interval, 1.40 to 3.11; P<0.001). For each additional copy of DEFA1A3, the odds of recurrent UTI in patients receiving antibiotic prophylaxis decreased by 47% when adjusting for vesicoureteral reflux grade and bowel and bladder dysfunction. In patients receiving placebo, DEFA1A3 copy number did not associate with risk of recurrent UTI. Notably, we found that DEFA1A3 is expressed in renal epithelium and not restricted to myeloid-derived cells, such as neutrophils. In conclusion, low DEFA1A3 copy number associated with recurrent UTIs in subjects in the RIVUR Study randomized to prophylactic antibiotics, providing evidence that copy number polymorphisms in an antimicrobial peptide associate with UTI risk.

SUBMITTER: Schwaderer AL

PROVIDER: S-EPMC5042661 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Polymorphisms in α-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux.

Schwaderer Andrew L AL Wang Huanyu H Kim SungHwan S Kline Jennifer M JM Liang Dong D Brophy Pat D PD McHugh Kirk M KM Tseng George C GC Saxena Vijay V Barr-Beare Evan E Pierce Keith R KR Shaikh Nader N Manak J Robert JR Cohen Daniel M DM Becknell Brian B Spencer John D JD Baker Peter B PB Yu Chack-Yung CY Hains David S DS

Journal of the American Society of Nephrology : JASN 20160303 10

The contribution of genetic variation to urinary tract infection (UTI) risk in children with vesicoureteral reflux is largely unknown. The innate immune system, which includes antimicrobial peptides, such as the α-defensins, encoded by DEFA1A3, is important in preventing UTIs but has not been investigated in the vesicoureteral reflux population. We used quantitative real-time PCR to determine DEFA1A3 DNA copy numbers in 298 individuals with confirmed UTIs and vesicoureteral reflux from the Rando ...[more]

PMID: 26940096

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Project description:BackgroundThe use of antibiotics for treating infection in childhood and their association with increased risk of asthma remain controversial. Infants diagnosed with vesicoureteral reflux (VUR) belong to a unique population who are administered antibiotics for a long time and are susceptible to recurrent UTI. It is interesting to study the risk of asthma in these infants with or without VUR.MethodsTaiwanese children born between 2000 and 2007 were enrolled in population-based birth cohort study. Participants diagnosed with VUR and UTI within first year were classified into four groups (VUR, UTI, VUR and UTI, and control). We calculated follow-up person-years for each participant from the index date until the asthma diagnosis, their withdrawal from the insurance system (because of death or loss to follow-up), or till the end of 2008. The risk of asthma was compared between the 4 cohorts by using Cox proportional hazards model analysis, adjusted hazard ratio (aHR), and 95% confidence interval (95% CI).ResultsChildren diagnosed with VUR (n = 350), UTI (n = 15542), VUR and UTI (n = 1696), and randomly selected controls (n = 17588) were enrolled. The overall rate of incidence of asthma was found to be 1.64-fold, 1.45-fold, and 1.17-fold higher in the UTI, VUR/UTI, and VUR cohorts than in the controls (5.60, 5.07, and 4.10 vs. 3.17 per 100 person-years), respectively. After adjusting the potential factors, the overall risk of asthma remained the highest in UTI (aHR: 1.74, 95% CI : 1.65 to 1.80) followed by VUR/UTI (aHR: 1.56, 95% CI : 1.40 to 1.75) and VUR cohorts (aHR: 1.25, 95% CI: 0.96 to 1.62). The incidence of asthma was higher in boys than in girls.ConclusionThe nationwide retrospective cohort study demonstrated that short-term therapeutic dose of antibiotics for UTI in infants with or without VUR has a positive correlation with the prevalence of childhood asthma. Significant risk of childhood asthma was not observed when VUR cohort was exposed to long-term low-dose of prophylactic antibiotics.

Dataset Information

Polymorphisms in ?-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux.

Publications

Polymorphisms in α-Defensin-Encoding DEFA1A3 Associate with Urinary Tract Infection Risk in Children with Vesicoureteral Reflux.

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