Ribonuclease 7 polymorphism rs1263872 reduces antimicrobial activity and associates with pediatric urinary tract infections
Keith R. Pierce, … , David S. Hains, John D. Spencer
Keith R. Pierce, … , David S. Hains, John D. Spencer
Published November 15, 2021
Citation Information: J Clin Invest. 2021;131(22):e149807. https://doi.org/10.1172/JCI149807.
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Concise Communication Infectious disease

Ribonuclease 7 polymorphism rs1263872 reduces antimicrobial activity and associates with pediatric urinary tract infections

Abstract

Ribonuclease 7 (RNase 7) is an antimicrobial peptide that prevents urinary tract infections (UTI); however, it is yet unknown how RNASE7 genetic variations affect its antimicrobial activity and its mitigation of UTI risk. This study determined whether the RNASE7 SNP rs1263872 is more prevalent in children with UTI and defined how rs1263872 affects RNase 7’s antimicrobial activity against uropathogenic E. coli (UPEC). We performed genotyping for rs1263872 in 2 national UTI cohorts, including children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux trial or the Careful Urinary Tract Infection Evaluation study. Genotypes from these cohorts were compared with those of female controls with no UTI. To assess whether rs1263872 affects RNase 7’s antimicrobial activity, we generated RNase 7 peptides and genetically modified urothelial cultures encoding wild-type RNase 7 and its variant. Compared with controls, girls in both UTI cohorts had an increased prevalence of the RNASE7 variant. Compared with the missense variant, wild-type RNase 7 peptide showed greater bactericidal activity against UPEC. Wild-type RNase 7 overexpression in human urothelial cultures reduced UPEC invasive infection compared with mutant overexpression. These results show that children with UTI have an increased prevalence of RNASE7 rs1263872, which may increase UTI susceptibility by suppressing RNase 7’s antibacterial activity.

Authors

Keith R. Pierce, Tad Eichler, Claudia Mosquera Vasquez, Andrew L. Schwaderer, Aaron Simoni, Steven Creacy, David S. Hains, John D. Spencer

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Figure 1

Distribution and odds ratio of minor RNASE7 allele in clinical cohorts.

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Distribution and odds ratio of minor RNASE7 allele in clinical cohorts. ...
(A) Relative percentage of each genotype across study cohorts. Female participants enrolled in the RIVUR (black bars, n = 424) and CUTIE (gray bars, n = 160) studies have a higher prevalence of GC and GG genotypes compared with controls (white bars, n = 482). 63.3% and 66.3% of participants in the RIVUR and CUTIE studies had the CC genotype, respectively. In contrast, 79.5% of controls had the CC genotype. (B) Odds ratios comparing the presence of the minor allele (influence on UTI risk) in different cohorts. Comparing the presence of the minor allele in the RIVUR cohort with that controls resulted in an odds ratio of 2.25 (95% CI 1.67–3.04, P < 0.0001). Comparing the presence of the minor allele in the CUTIE cohort and that in controls resulted in an odds ratio of 1.98 (95% CI 1.32–2.92, P = 0.0011). No difference was seen between the RIVUR and CUTIE cohorts (odds ratio 1.14, 95% CI 0.78–1.65), indicating that VUR status does not affect UTI risk in relation to genotype. All comparisons were made using Fisher’s exact test. **P < 0.01, ****P < 0.0001.