Genetic Variations and Development of Vesicoureteral Reflux and Sequelae

Research Inst Nationwide Children'S Hosp, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): Vesicoureteral reflux (VUR) nephropathy is the 4th leading etiology of end stage renal disease in children and affects 0.4-1.8% of all children. Researchers have begun to identify defects in renal development genes which result in VUR. However, factors other than the development of reflux might play an important role since many reflux patients are entirely asymptomatic while others develop renal scarring, hypertension and chronic kidney disease, usually following recurrent urinary tract infections (UTIs). The long-term objective of this proposal is to determine the precise role that genetics plays both in the development of VUR and its associated complications. Recently, investigators have begun to identify formidable host defense mechanisms, notably antimicrobial peptides (AMPs), which protect against UTIs. Recently, alterations in genes encoding AMPs have been reported due DNA structural alterations such as copy number variations (CNVs). These changes in DNA copy number can have profound effects on gene dosage, and alterations in DNA copy number play a key role in disease susceptibility or resistance. Since their recent discovery, CNVs in AMPs have been associated with susceptibility to Crohn's disease. The presence of AMPs in the urinary tract, similar the intestinal AMPs relevant to Crohns disease, suggests that AMP CNVs also contribute to UTI susceptibility. We hypothesize that the primary risk for recurrent UTI and subsequent renal scarring in VUR patients is altered gene dosage of antimicrobial peptide and chemokine genes, which may occur in conjunction with defects in renal development. To this end we will identify and compare the prevalence of candidate innate immunity and kidney development gene CNVs in patients with VUR with and without recurrent UTIs versus age and gender-matched controls using genome- wide CNV arrays (Specific Aim 1). This will be accomplished by analyzing DNA from patients enrolled in the RIVUR study (a randomized control trial analyzing antibiotic prophylaxis in children with VUR). In Specific Aim 2, we will perform exome sequence capture on a selected subset of patients to look for mutations in genes critical to innate immunity and kidney development. Finally, in Specific Aim 3, we will perform a sophisticated bioinformatic analysis of the genomic data and clinical data from the RIVUR study. These studies will result in novel information regarding the role of genetic variations in the development of VUR and its sequelae. Furthermore, they will provide the basis to identify "at risk" patients and therapeutic targets for immunomodulation. PUBLIC HEALTH RELEVANCE: Vesicoureteral reflux, or abnormal backflow of urine from the bladder to the kidneys, is a common childhood disease affecting 1% of all children, yet the genetic cause is unknown. Furthermore, only some patients with vesicoureteral reflux develop urinary tract infections and even fewer develop kidney problems because of these infections. Some research has suggested alterations in the DNA responsible for proteins, which function as our bodies'antibiotics might make some individuals prone to infections. By determining the role of antibiotic proteins in the urinary system's defense against infection, we will determine if these antibiotic proteins can be used to identify or treat people at risk for urinary tract infections. Also, we will investigate potential genetic causes of vesicoureteral reflux.