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

AM van Eerde, K Duran, E van Riel, CGF de Kovel, BPC Koeleman, NVAM Knoers, KY Renkema, HJR v.d. Horst, A Bokenkamp, JM van Hagen, LH van den Berg, Katja Wolffenbuttel, Joop Hoek, WF Feitz, TPVM de Jong, JC Giltay, C Wijmenga

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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, similar to 50% showed a clear-cut primary VUR phenotype and similar to 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.
Original languageUndefined/Unknown
JournalPLoS One (print)
Volume7
Issue number4
DOIs
Publication statusPublished - 2012

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