title: Genes in the ureteric budding pathway: association study on vesico-ureteral reflux patients.
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.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Albertien M
authors.initials: AM
authors.lastname: van Eerde
authors.forename: Karen
authors.initials: K
authors.lastname: Duran
authors.forename: Els
authors.initials: E
authors.lastname: van Riel
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Renkema
authors.forename: Henricus J R
authors.initials: HJ
authors.lastname: van der Horst
authors.forename: Arend
authors.initials: A
authors.lastname: Bökenkamp
authors.forename: Johanna M
authors.initials: JM
authors.lastname: van Hagen
authors.forename: Leonard H
authors.initials: LH
authors.lastname: van den Berg
authors.forename: Katja P
authors.initials: KP
authors.lastname: Wolffenbuttel
authors.forename: Joop
authors.initials: J
authors.lastname: van den Hoek
authors.forename: Wouter F
authors.initials: WF
authors.lastname: Feitz
authors.forename: Tom P V M
authors.initials: TP
authors.lastname: de Jong
authors.forename: Jacques C
authors.initials: JC
authors.lastname: Giltay
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
mesh_terms: D016022:Case-Control Studies; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D015810:Linkage Disequilibrium; D009024:Morphogenesis / Q000235:genetics*; D009426:Netherlands; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014513:Ureter / Q000196:embryology*; D060171:Uroplakin III / Q000235:genetics; D014718:Vesico-Ureteral Reflux / Q000235:genetics*; D000097905:Roundabout Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017027:Protein Tyrosine Phosphatases; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1; D060171:Uroplakin III; C486399:GREM1 protein, human; C498890:ROBO2 protein, human; D000097905:Roundabout Proteins; C508960:TGFB1 protein, human; C554660:UPK3A protein, human; C104381:EYA1 protein, human