Primary vesicoureteric reflux (VUR), the retrograde flow of urine from bladder to kidneys, is the most common urological anomaly in children. Associated primary and secondary renal lesions, known as reflux nephropathy, are the most common cause of childhood hypertension and renal failure, despite improvements in treatment of VUR. VUR is familial and highly genetically heterogeneous. We have recently performed a new genome-wide linkage and association scan of 225 families and control subjects using the 1.8 million markers on the Affymetrix SNP 6.0 chip. Results indicate numerous genomic regions of interest in Irish patients. We have combined our data with data from UK and Slovenian families, identified a region on Chromosome 10q as the major genetic locus for VUR in Europeans, and will investigate it with UK and Slovenian collaborators. A region of recessive linkage on 8q, containing just one gene, will be sequenced in three linked families. Evidence for linkage on Xp will also be pursued by sequencing. Our SNP genotyping data is also suitable for genomic copy-number variation (CNV) analysis. This does not apply to data from the UK and Slovenia, so for CNV analysis, we are collaborating with a group at Columbia University who have compatible data, to identify CNVs associated with VUR and reflux nephropathy. We have performed whole genome sequencing of members of a VUR family and identified the DNA variants most likely to be pathogenic; these will be investigated in cells by a colleague at Dublin City University. We have sequenced candidate gene ROBO2a and genes in our Chromosome 13 linkage peak in VUR index cases, and propose to complete these studies. We are also sub-classifying clinical data in renal scans of our patients to leverage our genome scan data to investigate the genetics of which VUR patients develop reflux nephropathy and which do not.
