A genome-wide scan for genes involved in primary vesicoureteric reflux

Abstract

Background: Vesicoureteric reflux (VUR) is the retrograde flow of urine from the bladder into the ureters. It is the most common urological anomaly in children, and a major cause of end-stage renal failure and hypertension in both children and adults. VUR is seen in approximately 1-2% of Caucasian newborns and is frequently familial. Objective and methods: In order to search for genetic loci involved in VUR, we performed a genome-wide linkage scan using 4710 single-nucleotide polymorphisms (SNPs) in 609 individuals from 129 Irish families with .1 affected member. Results: Nonparametric linkage (NPL) analysis of the dataset yielded moderately suggestive linkage at chromosome 2q37 (NPL max = 2.67, p,0.001). Analysis of a subset without any additional features, such as duplex kidneys, yielded a maximum NPL score of 4.1 (p = 0.001), reaching levels of genome-wide statistical significance. Suggestive linkage was also seen at 10q26 and 6q27, and there were several smaller peaks. Conclusion: Our results confirm the previous conclusion that VUR is genetically heterogeneous, and support the identification of several disease-associated regions indicated by smaller studies, as well as indicating new regions of interest for investigation.

Genetics of vesicoureteral reflux

“…the results specifically demonstrated that PAX2, GFRA1 and EMX2 were present in two copies in 8 cases suggesting that one or more novel genes for urinary tract development and for genital development reside in this region. 131 special attention should be drawn to the region on chromosome 13q32-q33, which was not the highest peak in the study by Kelly et al 47 but received support from two other linkage studies 22,127 and a study of chromo somal rearrangements. 132 it is particularly noteworthy that a genome-wide linkage scan for end-stage renal disease (esrD) 130 and a candidate gene association study for chronic kidney disease (CKD) 133 provide further data to support a role for this region in renal disease or CaKut.…”

“…43,44 the part of the mesonephric duct between newly developed ureter and urogenital sinus is subsequently removed by apoptosis, 45 whereupon the free end of the developing ureter inserts into the bladder wall and the vesicoureteric valve is formed. 41,46,47 the mechanism of vur and subsequent reflux nephro pathy is based on the disruption of a proper valvular mechanism at the vesicoureteric junction, which leads to retrograde flow of urine into the ureter or kidney. this disruption is most likely the result of a shortened intravesical ureter, and an enlarged or malpositioned ureteric orifice.…”

“…24 in 2007, Kelly et al 47 carried out a genome-wide scan investigating 609 individuals from 129 irish families with more than one affected member with vur and reported that nonparametric linkage (nPL) analysis revealed a region on chromosome 2q37, reaching genome-wide statistical significance,when families with duplex kidneys were removed from the analysis. Data regarding linkage with regions identified in this study on chromosomes 2, 3, 4, 10, 13, 16 and 20 were supported by smaller linkage studies or studies of chromosomal rearrangements associated with vur, usually in association with other urinary tract malformations.…”

“…22,47,129 However, dominant as well as recessive models were used to analyze 72 vur-affected individuals from 12 large families in a study by weng et al 26 whereas the dominant model yielded no signals across the entire genome, a unique linkage peak on chromosome 12p11-q13 was found in the recessive model and was confirmed by fine mapping. 26 although the clinically observed increased risk of vur in siblings of index cases and the high transmission from parents to children suggest that vur is not generally inherited in a recessive fashion, the data suggest that there may be a recessive form of the disorder.…”

Whole-Genome Linkage and Association Scan in Primary, Nonsyndromic Vesicoureteric Reflux

“…Subsequent studies using similar kindreds 10 -12 have supported the notion that the condition is genetically heterogeneous. In the largest linkage study of VUR before this report, Kelly et al 13 performed a linkage genome scan of 609 individuals (283 affected individuals in 129 families) and detected six to seven regions with suggestive evidence of linkage, 14 one of which at chromosome 2q37 attained genome-wide significance when analyzed in a phenotypically derived subset of the data. The high incidence in offspring of affected individuals and the large number of pedigrees consistent with autosomal dominant inheritance, albeit with reduced penetrance, is in keeping with a dominant model; however, recently, a locus was identified on 12p11-q13 using a recessive model.…”