Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux
Miguel VerbitskyPriya KrithivasanEkaterina BatourinaAtlas KhanSarah E. GrahamMaddalena MarasàHyun-Woo KimTze Y. LimPatricia L. WengElena SánchezAdele MitrottiDina AhramFrancesca ZanoniDavid FaselRik WestlandMatthew G. SampsonJun Y. ZhangMonica BodriaByum Hee KilShirlee ShrilLoreto GesualdoFabio TorriFrancesco ScolariClaudia IzziJ. A. E. van WijkMarijan SaragaDomenico SantoroGiovanni ContiDavid BartonMark G. DobsonPrem PuriSusan L. FurthBradley A. WaradyIsabella PisaniEnrico FiaccadoriLandino AllegriM. L. Degl’InnocentiGiorgio PiaggioShumyle AlamMaddalena GiganteGianluigi ZazaPasquale EspositoFangming LinAna Cristina Simões e SilvaAndrzej BrodkiewiczDorota DrożdżKatarzyna ZachwiejaMonika MiklaszewskaMaria SzczepańskaPiotr AdamczykMarcin TkaczykDaria TomczykPrzemysław SikoraMałgorzata Mizerska-WasiakGrażyna KrzemieńAgnieszka SzmigielskaMarcin ZaniewVladimir J. LozanovskiZoran GucevIuliana Ionita‐LazaIan B. StanawayDavid R. CrosslinCraig S. WongFriedhelm HildebrandtJonathan BaraschEimear E. KennyRuth J. F. LoosBrynn LevyGian Marco GhiggeriHákon HákonarsonAnna Latos‐BieleńskaAnna Materna‐KirylukJohn M. DarlowVelibor TasićCristen J. WillerKrzysztof KirylukSimone Sanna‐CherchiCathy MendelsohnAli G. Gharavi
27
Citation
99
Reference
10
Related Paper
Citation Trend
Abstract:
Significance Statement Vesicoureteral reflux (VUR) is associated with progressive kidney disease. Familial aggregation supports a hereditary basis; however, its genetic architecture remains to be elucidated. The largest VUR copy number variant analysis and genome-wide association study to date accounts for multiple modes of inheritance and sex-specific effects in VUR, identifying three study-wide significant and five suggestive loci with large effects, containing canonical developmental genes including WDPCP and WNT5A . Results of experiments in mice support novel roles of Wnt5a in urogenital development. Altogether, 6% of patients carried high-risk genotypes. These findings have important implications for VUR screening. Background Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major 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 =6.35×10 −8 ) The GWAS identified three study-wide 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, and WNT5A ). 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 =1.86×10 –9 ). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. 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.Keywords:
Genome-wide Association Study
Cite
Citations (27)
A model was designed to study the relation between urinary infection and vesicoureteral, low-grade, total reflux. Surgical alteration of the ureterovesical junction produced grade 2 vesicoureteral reflux in seven of 13 animals. In the other six animals, surgery had rendered the vesicoureteral junction marginally competent and chronic bladder infection caused grade 2 reflux. It was found that grade 2 vesicoureteral reflux in the adult monkey neither prolongs urinary tract infection nor causes continued renal infection.
Chronic pyelonephritis
Cite
Citations (12)
When the standard cystogram does not show vesicoureteral reflux in children who have experienced febrile urinary tract infections (UTIs), clinical management is controversial. We postulated that vesicoureteral reflux accounts for such UTIs but is "occult." We tested this hypothesis by using a novel method, PIC cystography (Positioning the Instillation of Contrast at the ureteral orifice) at the time of cystoscopy.We performed PIC cystography with instillation of contrast medium at the ureteral orifice consecutively and prospectively in 57 children who underwent cystoscopy between November 1999 and February 2002 to evaluate febrile UTIs in 40 patients, dysfunctional voiding in 14 and hydronephrosis in 3. The control group (27 patients, 54 renal units) was used to assess the accuracy of PIC by comparing the results against those with the standard cystogram in children who did not have febrile infection and did not demonstrate vesicoureteral reflux (15 patients, 30 renal units), and in those who had febrile infection and vesicoureteral reflux (12 patients, 24 renal units). The study group (30 patients, 60 renal units) served to assess the incidence of "occult" vesicoureteral reflux in children who experienced febrile UTIs yet did not have vesicoureteral reflux on standard cystography.In children without febrile UTIs all 30 ureteral orifices had a normal endoscopic appearance and no vesicoureteral reflux by PIC cystography. In children with febrile UTIs 15 ureteral orifices with known vesicoureteral reflux were lateral and/or patulous and demonstrated vesicoureteral reflux by PIC, 4 appeared normal and did not exhibit vesicoureteral reflux on standard cystography or by PIC, and 5 were lateral and/or patulous in appearance and did not display vesicoureteral reflux on standard cystography, but did show vesicoureteral reflux by PIC. These findings reveal that PIC cystography is 100% sensitive at demonstrating reflux already known by standard cystogram, is 87% specific as it showed reflux in 5 of 39 renal units not revealed by a standard cystogram and has an overall accuracy of 91%.At cystoscopy all 30 children demonstrated an abnormal appearance of one or both ureteral orifices. PIC cystography showed vesicoureteral reflux in all 30 children (48 renal units, 12 unilateral and 18 bilateral). The remaining ureteral orifices (12), which appeared normal, did not permit vesicoureteral reflux. Children with vesicoureteral reflux by PIC were treated with antimicrobial prophylaxis (26) or ureteral reimplantation (4, 2 unilateral and 2 bilateral reimplantation) Postoperatively, these children did not experience a febrile UTI during followup (average 8 months).PIC cystography is simple to perform using routinely available operating room equipment and does not artifactually induce vesicoureteral reflux. The incidence of "occult" vesicoureteral reflux in children who experience febrile UTIs without vesicoureteral reflux on standard cystography is 100% by PIC cystography. PIC cystography should be done when vesicoureteral reflux is suspected in children who experience febrile UTIs but do not exhibit reflux on standard cystography.
Cystography
Voiding cystourethrogram
Occult
Cite
Citations (66)
Studies of vesicoureteral reflux in a primate model were reviewed. Reflux was found to be uncommon in adults but frequent in infants, suggesting that maturation of the ureterovesical junction occurs. Repeated bladder infections did not prevent this maturation. Infection did not cause reflux unless the junction was only marginally competent. Reflux prolonged urinary tract infection in the infant, but in the adult monkey it did not.
Cite
Citations (10)
Cite
Citations (271)
On the basis of the urethrographic examinations of 3,505 infants and children, the author evaluates the relationship of vesicoureteral reflux to urinary tract obstruction, urinary tract infection, and renal atrophy. He concludes that (1) urinary tract infection is the most common cause of vesicoureteral reflux; (2) no proof exists that vesicoureteral reflux either causes or propagates urinary tract infection; (3) medical management is the treatment of choice for infection and vesicoureteral reflux; (4) surgery is not indicated in the treatment of urinary tract infection and vesicoureteral reflux.
Cite
Citations (37)
Vesicoureteral reflux in siblings or different generations has not been emphasized. In nine families, each with two members having unilateral or bilateral reflux, at least one member from each family has required surgical correction. Family surveys demonstrated other congenital and acquired urinary tract abnormalities. Failure of conservative management plus cystoscopic evidence of a defective ureteral orifice support a familial or hereditary basis for vesicoureteral reflux.
Cite
Citations (19)
An operative procedure for the repair of primary vesicoureteral reflux in 51 children (83 renal units) is described, its merits are discussed and its advantages are stressed. Reflux was prevented in 90.2 per cent of the children and 74.5 per cent of the patients remained free of infection. No obstruction has occurred in our series as compared to a 5 per cent incidence rate in cases of ureteroneocystostomy. Our procedure is not recommended for megaureters with reflux or for recurrent vesicoureteral reflux.
Cite
Citations (12)
Maldevelopment
Reflux nephropathy
Cite
Citations (34)
Background : Treatment of vesicoureteral reflux by endoscopic injection of Teflon paste has recently demonstrated a good success rate. This report describes our experience in treating vesicoureteral reflux in children with particular reference to follow‐up data. Methods : Between December 1993 and November 1994, endoscopic injection of Teflon paste into the submucosa was performed on 18 children (29 ureters) to correct vesicoureteral reflux. Results : After treatment, reflux was eliminated in 75.9%, decreased in 1 3.8%, and unchanged in 1 0.3% of the ureters. The success rate was lower for high grade reflux cases and ureteral orifices with abnormal shapes. Conclusion : Long‐term follow‐up for up to 2 years demonstrated that although late recurrence may occur in a small proportion of cases, the procedure is safe, simple and effective for correcting vesicoureteral reflux.
Submucosa
Endoscopic treatment
Cite
Citations (10)