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

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.