title: Polymorphisms in α-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 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 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.
authors.affiliation: The Centers for Clinical and Translational Medicine and.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Schwaderer
authors.affiliation: The Centers for Clinical and Translational Medicine and.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Departments of Biostatistics and.
authors.forename: SungHwan
authors.initials: S
authors.lastname: Kim
authors.affiliation: Emergency Medicine and.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kline
authors.affiliation: Innate Immunity Translational Research Center, Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, Tennessee.
authors.forename: Dong
authors.initials: D
authors.lastname: Liang
authors.affiliation: Division of Nephrology, Department of Pediatrics, University of Iowa Children's Hospital, Iowa City, Iowa.
authors.forename: Pat D
authors.initials: PD
authors.lastname: Brophy
authors.affiliation: Division of Anatomy, The Ohio State University, Columbus, Ohio.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: McHugh
authors.affiliation: Departments of Biostatistics and.
authors.forename: George C
authors.initials: GC
authors.lastname: Tseng
authors.affiliation: The Centers for Clinical and Translational Medicine and.
authors.forename: Vijay
authors.initials: V
authors.lastname: Saxena
authors.affiliation: The Centers for Clinical and Translational Medicine and.
authors.forename: Evan
authors.initials: E
authors.lastname: Barr-Beare
authors.affiliation: Innate Immunity Translational Research Center, Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, Tennessee.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Pierce
authors.affiliation: Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Nader
authors.initials: N
authors.lastname: Shaikh
authors.affiliation: Departments of Biology and Pediatrics, University of Iowa, Iowa; and.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Manak
authors.affiliation: Emergency Medicine and.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cohen
authors.affiliation: The Centers for Clinical and Translational Medicine and.
authors.forename: Brian
authors.initials: B
authors.lastname: Becknell
authors.affiliation: The Centers for Clinical and Translational Medicine and.
authors.forename: John D
authors.initials: JD
authors.lastname: Spencer
authors.affiliation: Department of Pathology, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Baker
authors.affiliation: Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Chack-Yung
authors.initials: CY
authors.lastname: Yu
authors.affiliation: Innate Immunity Translational Research Center, Children's Foundation Research Institute at Le Bonheur Children's Hospital, Memphis, Tennessee; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee dhains@uthsc.edu.
authors.forename: David S
authors.initials: DS
authors.lastname: Hains
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010456:Peptides, Cyclic / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014552:Urinary Tract Infections / Q000209:etiology / Q000235:genetics*; D014718:Vesico-Ureteral Reflux / Q000150:complications / Q000235:genetics*; D023084:alpha-Defensins / Q000235:genetics / Q000502:physiology*
chemical_list: C429483:DEFA1A3 protein, human; D010456:Peptides, Cyclic; D023084:alpha-Defensins
keywords: genetics and development; pyelonephritis; vesico-ureteral reflux