Abstract: SA-PO619

Genetic Alterations in DMBT Confer Urinary Tract Infection Risk in Children and Mice

Session Information

Category: Genetic Diseases of the Kidney

  • 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases

Authors

  • Schwaderer, Andrew L., The Ohio State University, Westerville, Ohio, United States
  • Hains, David S., Riley Children's Hospital, Indianapolis, Indiana, United States
  • Ketz, John, Nationwide Children''s Hospital, Columbus, Ohio, United States
  • Hollox, Ed, University of Leicester, Leicester, United Kingdom
Background

The deleted in malignant brain tumor 1 (DMBT1) gene is prone to copy number variation (CNV) that alters the number of bacteria-binding domains in 2 distinct gene regions (CNV1 and CNV2). DMBT1's role in urinary tract functions (UTI) has not been previously evaluated

Methods

RIVUR study children with UTI and vesicoureteral reflux treated with antibiotics vs. placebo were studied. Copy number estimates for CNV1 and CNV2 were determined using a paralogue ratio test (PRT). Experimental UTI was induced by transurethral inoculation of uropathogenic E.coli (UPEC) into Dmbt1-/- vs wild-type mice. DMBT1-UPEC aggregation was evaluated by evaluating differential GFP expressing UPEC aggregation in the bottom of wells coated with DMBT versus control.

Results

DNA samples from 314 Caucasian children (159 in antibiotic prophylaxis group and 155 in the placebo group) were typed for DMBT1 CNV1 and CNV2. Higher copy number of CNV2 (but not CNV1) was associated with fewer infections (p=.007), particularly in the prophylaxis group (Figure). Compared to wild type mice, Dmbt1-/- mice had 5-fold higher bladder bacterial burdens (cfu/bladder) at 6 hrs following following low (107UPEC) inoculum and a 2.4-fold higher UPEC bladder burden at 6 hrs following a high (108 UPEC) inoculum; p values were 0.04 and 0.01 respectively. Kidney UPEC burdens were not different between Dmbt1-/- and wild-type mice. Additionally, DMBT protein, but not control resulted in bacterial clumping in our bacterial agglutination assay.

Conclusion

Our results indicate that children with low copy number of DMBT1 CNV2 would benefit from antibiotic prophylaxis. Increased murine bladder bacterial burdens in Dmbt1-/- mice compared to wild type and increased UPEC agglutination with DMBT demonstrates it’s functional relevance in the innate immune defense against UTI.

Funding

  • NIDDK Support