Linkage analysis of candidate genes in families with vesicoureteral reflux

Vesicoureteral reflux familial clustering implies that genetic factors have a key role in reflux pathogenesis. We identified genes that cause this disease and elucidated the biology and genetics of vesicoureteral reflux.

There were 166 families and 738 individuals, including 319 parents and 419 offspring. The 166 families had 193 affected sib pairs in whom vesicoureteral reflux was confirmed by voiding cystourethrogram. DNA samples were obtained to analyze various candidate genes or regions with a key role in urinary tract development, eg UPK3, UPK2, UPK1B, Chr.10q25.3, KAL1, PAR1 and PAR2. A genome scan was completed in 133 families and the results of genome scan single nucleotide polymorphisms in or closely flanking the candidate genes were investigated. Fine mapping was done to narrow the significant regions and identify potential candidate genes.

Lod scores based on the model, proposing a single dominant locus with decreased penetrance, were negative at all loci. Marginally significant nonparametric lod scores were seen at several loci, particularly UPK1B and PAR1. A signal of moderate significance was detected at the region centered on 10q 25.2.

Linkage analysis in a large cohort of vesicoureteral reflux families ruled out UPK3, UPK2, UPK1B, KAL, PAR1 and PAR2 as candidate genes for reflux. Results provide evidence supporting genes and regions that may be worth further study as primary vesicoureteral reflux loci.