Genes in the Ureteric Budding Pathway: Association Study on Vesico-Ureteral Reflux Patients

Albertien M Van Eerde,Karen Duran,Carolien G F De Kovel,Joop Van Den Hoek,Leonard H Van Den Berg,Tom P V M De Jong,Kirsten Y Renkema,Nine V A M Knoers,Johanna M Van Hagen,Arend Bökenkamp,Jacques C Giltay,Cisca Wijmenga,Wouter F Feitz,Bobby P C Koeleman,Els Van Riel,Henricus J R Van Der Horst,Katja P Wolffenbuttel

doi:10.1371/journal.pone.0031327

Abstract

Vesico-ureteral reflux (VUR) is the retrograde passage of urine from the bladder to the urinary tract and causes 8.5% of end-stage renal disease in children. It is a complex genetic developmental disorder, in which ectopic embryonal ureteric budding is implicated in the pathogenesis. VUR is part of the spectrum of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). We performed an extensive association study for primary VUR using a two-stage, case-control design, investigating 44 candidate genes in the ureteric budding pathway in 409 Dutch VUR patients. The 44 genes were selected from the literature and a set of 567 single nucleotide polymorphisms (SNPs) capturing their genetic variation was genotyped in 207 cases and 554 controls. The 14 SNPs with p<0.005 were included in a follow-up study in 202 cases and 892 controls. Of the total cohort, ∼50% showed a clear-cut primary VUR phenotype and ∼25% had both a duplex collecting system and VUR. We also looked for association in these two extreme phenotype groups. None of the SNPs reached a significant p-value. Common genetic variants in four genes (GREM1, EYA1, ROBO2 and UPK3A) show a trend towards association with the development of primary VUR (GREM1, EYA1, ROBO2) or duplex collecting system (EYA1 and UPK3A). SNPs in three genes (TGFB1, GNB3 and VEGFA) have been shown to be associated with VUR in other populations. Only the result of rs1800469 in TGFB1 hinted at association in our study. This is the first extensive study of common variants in the genes of the ureteric budding pathway and the genetic susceptibility to primary VUR.

Highlights

Vesico-ureteral reflux [VUR (MIM 193000)] is the retrograde passage of urine from the bladder into the upper urinary tract
We set out to genotype the top 14 single nucleotide polymorphisms (SNPs), which mapped to RARB, ROBO2, EYA1, GFRA1, GREM1 and UPK3A, in stage two (Table 1)
A cohort of VUR patients was screened for association with tag SNPs covering 44 candidate genes (Table S1) that are related to ureteric budding function (Schedl [60]: figure 3: http://www. nature.com/nrg/journal/v8/n10/fig_tab/nrg2205_F3.html#figuretitle)

Summary

Introduction

Vesico-ureteral reflux [VUR (MIM 193000)] is the retrograde passage of urine from the bladder into the upper urinary tract. It is one of the most commonly detected congenital anomalies and probably has a conservatively estimated prevalence of 1%. Most children grow out of the disorder without serious morbidity, a subset does develop long-term complications. In this group VUR results in renal damage, either as a result of ascending urinary tract infections (reflux nephropathy) or of renal hypo- or dysplasia, which is often associated with VUR. In these two groups VUR accounts for 7.4 – 9.6% and 8.8 – 13.8%, respectively, of end-stage renal disease in Dutch children. [4]

Methods

Results

Conclusion