Genome gender diversity in affected sib‐pairs with familial vesico‐ureteric reflux identified by single nucleotide polymorphism linkage analysis

Abstract

Study Type – Aetiology (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Genetic linkage to distinguish loci for VUR has been previously described in several autosomal chromosomes. Although there are numerous explanations for the dissimilar findings, e.g. multifactorial etiology of VUR and hereditary miscellany among studied populations, clinical diversity between males and females may indicate a central gender‐specific genetic susceptibility. Early studies suggested the presence of modified VUR gene(s) on the X‐chromosome, accounting for the higher incidence of this disorder among female members in the pedigrees studied. On the other hand male‐to‐male transmission and a higher ratio of females to males argued against X‐linked inheritance. More recently, additional chromosomal regions (i.e. chromosomes 1–7, 10–13, and 18–22) have been identified for VUR by using single nucleotide polymorphism‐genome‐wide linkage analysis. This is the first study to show that there is autosomal difference in VUR expression in males and females. This genotype variability may be the basis for the clinical differences between genders in children with VUR. OBJECTIVE To assess gender‐specific genetic differences in the susceptibility loci for vesico‐ureteric reflux (VUR) in families who have two or more affected children. PATIENTS AND METHODS A genome‐wide linkage analysis of VUR with high‐density single nucleotide polymorphisms was conducted in 98 families with two or more affected children. A total of 221 affected offspring (123 sibling pairs) were included in the analysis. Genomic DNA was extracted from blood or saliva from all the patients. Data was stratified and analysed according to clinical presentation and gender of the proband and affected siblings. RESULTS Using the affected sib‐pair method, statistically significant peaks were found on chromosomes 1 (logarithm of odds, base10 [LOD] 4.4) and 5 (LOD 3.7) in males and on chromosomes 3 (LOD 3.5), 13 (LOD 4.5), and 15 (LOD 3.4) in females. CONCLUSION This genotype variability might be the basis for the clinical differences between genders in children with VUR. Our data might be the first step to understanding the genetic background behind the gender‐specific differences of VUR and more clearly defining the genetically different subgroups of VUR.

Clinical characteristics and outcome of childhood vesicoureteral reflux

“…It has been known that girls with VUR generally present with UTIs and infant boys are generally diagnosed during investigations for congenital urinary abnormalities. 8 Similarly, in our study boys were diagnosed at younger ages and AHN was more common among them. Moreover, boys had greater degrees of reflux and more frequent abnormal radiological findings.…”

A new genome scan for primary nonsyndromic vesicoureteric reflux emphasizes high genetic heterogeneity and shows linkage and association with various genes already implicated in urinary tract development

“…; Marchini et al. ), array‐based comparative genomic hybridization (Weber et al. ), and gene expression studies (McMahon et al.…”

“…However, for nonsyndromic VUR, mutations accounting for only a small proportion of cases have been found, and most of these were in patients with CAKUT (PAX2 [Nishimoto et al 2001], UPK3A [Jenkins et al 2005;Schonfelder et al 2006], UPK2 [Jenkins et al 2006], HNF1B(TCF2) [Weber et al 2006], ROBO2 [Lu et al 2007;Bertoli-Avella et al 2008], SIX2 [Weber et al 2008], BMP4 [Weber et al 2008], SOX17 [Gimelli et al 2010] and TNXB [Gbadegesin et al 2013]). Studies to search for genes involved in primary nonsyndromic VUR and/or CAKUT have included association, linkage, and exon-sequencing studies of candidate genes ( [Jenkins et al 2007;Saisawat et al 2012; van Eerde et al 2012] and references within reviews [Murawski and Gupta 2006;Song and Yosypiv 2011]), genome-wide linkage and association studies (Feather et al 2000;Kelly et al 2007;Sanna-Cherchi et al 2007;Conte et al 2008;Weng et al 2009;Briggs et al 2010;Cordell et al 2010;Marchini et al 2012), array-based comparative genomic hybridization (Weber et al 2011), and gene expression studies (McMahon et al 2008).…”

Características clínicas y evolución del reflujo vesicoureteral en la infancia

“…Se sabe que las niñas con RVU en general tienen infección urinaria, mientras que los lactantes masculinos suelen recibir el diagnóstico durante el estudio de anomalías urinarias congénitas. 8 De manera similar, en nuestro estudio, a los varones se los diagnosticó a una edad más temprana, y la HNP fue más frecuente entre ellos. Asimismo, estos tuvieron grados más altos de reflujo y mayor cantidad de hallazgos radiológicos anómalos.…”