Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
PLoS One. 2012;7(4):e31327. doi: 10.1371/journal.pone.0031327. Epub 2012 Apr 27.
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.
膀胱输尿管反流（VUR）是尿液从膀胱逆行到尿路的现象，导致 8.5%的儿童患有终末期肾病。它是一种复杂的遗传发育障碍，其中异位胚胎输尿管芽生被认为是发病机制的一部分。VUR 是先天性肾和尿路异常（CAKUT）谱的一部分。我们使用两阶段病例对照设计，对 449 名荷兰 VUR 患者的输尿管芽生途径中的 44 个候选基因进行了广泛的关联研究。这 44 个基因是从文献中选择的，一组 567 个单核苷酸多态性（SNP）捕获了它们的遗传变异，在 207 例病例和 554 例对照中进行了基因分型。在包含 202 例病例和 892 例对照的后续研究中，纳入了 14 个 p 值<0.005 的 SNP。在总队列中，约 50%的患者表现出明显的原发性 VUR 表型，约 25%的患者既有双肾盂系统又有 VUR。我们还在这两个极端表型组中寻找关联。没有一个 SNP 达到显著的 p 值。四个基因（GREM1、EYA1、ROBO2 和 UPK3A）中的常见遗传变异显示出与原发性 VUR（GREM1、EYA1、ROBO2）或双肾盂系统（EYA1 和 UPK3A）发展相关的趋势。三个基因（TGFB1、GNB3 和 VEGFA）中的 SNP 已被证明与其他人群中的 VUR 相关。只有 TGFB1 中的 rs1800469 结果提示我们的研究存在关联。这是对输尿管芽生途径基因中的常见变异与原发性 VUR 的遗传易感性进行的首次广泛研究。
