engleski

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux

Background: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and amajor cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. Methods: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. Results: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12 ; 95% CI, 2.10 to 4.54 ; P=6.35x10(-8)) TheGWAS identified three studywide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, andWNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890 ; OR, 3.65 ; 95% CI, 2.39 to 5.56 ; P=1.86x10(-9)). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis ofWnt5amutant mice confirmedthe roleofWnt5a signaling inbladder and uretericmorphogenesis. Conclusions: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

vesico-ureteral reflux ; human genetics ; genetics and development ; pediatric nephrology

nije evidentirano