In this proposal, we will undertake a comprehensive approach to study the genetic basis of Vesicoureteral reflux (VUR). VUR has a prevalence of 1-2% in the Caucasian population and can account for up to 25-30% of pediatric and 10% of adult end stage renal disease (ESRD). Except for a few rare cases however, the specific genetic defects responsible for VUR are not known. To date, only a limited number of approaches have been explored to solve the genetic basis of VUR. In recent years, we have successfully applied GWAS, CNV analysis and exome sequencing to identify novel genes and loci for diverse renal and urological traits. Here, we will apply these approaches to resolve the genetic architecture of VUR. We hypothesize that familial VUR is genetically heterogeneous and caused by rare variants with large effect, which will be identifiable by linkage analysis combined with exome sequencing. Furthermore, we hypothesize that sporadic forms of VUR are produced by the combined effects of rare and common variants that will be detectable by GWAS methodology, CNV analysis and targeted resequencing of genes discovered in familial VUR. The study benefits from our own unique cohorts of patients with familial and sporadic VUR, multiple genotyped VUR cohorts contributed by collaborating institutions, as well as a national cohort contributed by the RIVUR study.
In aim 1, we will identify rare mutations contributing to familial VUR by linkage analysis combined with exome sequencing in 50 kindreds.
In aim 2, we will genotype the RIVU cohort and combine with other genotyped cohorts to identify rare genomic imbalances and common SNP variants for sporadic VUR.
In aim 3, we will perform genotype-phenotype correlations of common and rare variants contributing to VUR.
VUR accounts for up to 25-30% of pediatric and 10% of adult end stage renal disease (ESRD). Understanding the genetic basis of disease can provide insight into the pathogenesis of disease, identify new noninvasive methods for diagnosis and help develop tools for predicting prognosis.
| Wang, Xueqiao; Zheng, Xiaoqing; Zhang, Juanlian et al. (2018) Physiological functions of ferroportin in the regulation of renal iron recycling and ischemic acute kidney injury. Am J Physiol Renal Physiol 315:F1042-F1057 |
| Sanna-Cherchi, Simone; Westland, Rik; Ghiggeri, Gian Marco et al. (2018) Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest 128:4-15 |
| Joseph, Diya B; Chandrashekar, Anoop S; Abler, Lisa L et al. (2018) In vivo replacement of damaged bladder urothelium by Wolffian duct epithelial cells. Proc Natl Acad Sci U S A 115:8394-8399 |
| Kiryluk, Krzysztof; Bomback, Andrew S; Cheng, Yim-Ling et al. (2018) Precision Medicine for Acute Kidney Injury (AKI): Redefining AKI by Agnostic Kidney Tissue Interrogation and Genetics. Semin Nephrol 38:40-51 |
| Park, Jihwan; Shrestha, Rojesh; Qiu, Chengxiang et al. (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758-763 |
| Sanna-Cherchi, Simone; Khan, Kamal; Westland, Rik et al. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. Am J Hum Genet 101:789-802 |
| Costanzo, Maria Rosa; Ronco, Claudio; Abraham, William T et al. (2017) Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure: Current Status and Prospects for Further Research. J Am Coll Cardiol 69:2428-2445 |
| Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754 |
| Verbitsky, Miguel; Kogon, Amy J; Matheson, Matthew et al. (2017) Genomic Disorders and Neurocognitive Impairment in Pediatric CKD. J Am Soc Nephrol 28:2303-2309 |
| Werth, Max; Schmidt-Ott, Kai M; Leete, Thomas et al. (2017) Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts. Elife 6: |
Showing the most recent 10 out of 14 publications
