Polymorphisms in α-defensin-encoding DEFA1A3 associate with urinary tract infection risk in children with vesicoureteral reflux

Andrew L. Schwaderer, Huanyu Wang, Sung Hwan Kim, Jennifer M. Kline, Dong Liang, Pat D. Brophy, Kirk M. McHugh, George C. Tseng, Vijay Saxena, Evan Barr-Beare, Keith R. Pierce, Nader Shaikh, J. Robert Manak, Daniel M. Cohen, Brian Becknell, John D. Spencer, Peter B. Baker, Chack Yung Yu, David Hains

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 a-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.

Original languageEnglish (US)
Pages (from-to)3175-3186
Number of pages12
JournalJournal of the American Society of Nephrology
Volume27
Issue number10
DOIs
StatePublished - Jan 1 2016

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Defensins
Vesico-Ureteral Reflux
Urinary Tract Infections
Urinary Bladder
DNA Copy Number Variations
Placebos
Anti-Bacterial Agents
Kidney
Peptides
Antibiotic Prophylaxis
Myeloid Cells
Cicatrix
Real-Time Polymerase Chain Reaction
Immune System
Neutrophils
Epithelium
Odds Ratio
Confidence Intervals
DNA
Population

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Polymorphisms in α-defensin-encoding DEFA1A3 associate with urinary tract infection risk in children with vesicoureteral reflux. / Schwaderer, Andrew L.; Wang, Huanyu; Kim, Sung Hwan; Kline, Jennifer M.; Liang, Dong; Brophy, Pat D.; McHugh, Kirk M.; Tseng, George C.; Saxena, Vijay; Barr-Beare, Evan; Pierce, Keith R.; Shaikh, Nader; Manak, J. Robert; Cohen, Daniel M.; Becknell, Brian; Spencer, John D.; Baker, Peter B.; Yu, Chack Yung; Hains, David.

In: Journal of the American Society of Nephrology, Vol. 27, No. 10, 01.01.2016, p. 3175-3186.

Research output: Contribution to journalArticle

Schwaderer, AL, Wang, H, Kim, SH, Kline, JM, Liang, D, Brophy, PD, McHugh, KM, Tseng, GC, Saxena, V, Barr-Beare, E, Pierce, KR, Shaikh, N, Manak, JR, Cohen, DM, Becknell, B, Spencer, JD, Baker, PB, Yu, CY & Hains, D 2016, 'Polymorphisms in α-defensin-encoding DEFA1A3 associate with urinary tract infection risk in children with vesicoureteral reflux', Journal of the American Society of Nephrology, vol. 27, no. 10, pp. 3175-3186. https://doi.org/10.1681/ASN.2015060700
Schwaderer, Andrew L. ; Wang, Huanyu ; Kim, Sung Hwan ; Kline, Jennifer M. ; Liang, Dong ; Brophy, Pat D. ; McHugh, Kirk M. ; Tseng, George C. ; Saxena, Vijay ; Barr-Beare, Evan ; Pierce, Keith R. ; Shaikh, Nader ; Manak, J. Robert ; Cohen, Daniel M. ; Becknell, Brian ; Spencer, John D. ; Baker, Peter B. ; Yu, Chack Yung ; Hains, David. / Polymorphisms in α-defensin-encoding DEFA1A3 associate with urinary tract infection risk in children with vesicoureteral reflux. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 10. pp. 3175-3186.
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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 a-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.",
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