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Genome-wide association study in patients with posterior urethral valves.

ABSTRACT: Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance (P < 1 × 10^-5). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations.

SUBMITTER: van der Zanden LFM

PROVIDER: S-EPMC9552614 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Genome-wide association study in patients with posterior urethral valves.

van der Zanden Loes F M LFM Maj Carlo C Borisov Oleg O van Rooij Iris A L M IALM Quaedackers Josine S L T JSLT Steffens Martijn M Schierbaum Luca L Schneider Sophia S Waffenschmidt Lea L Kiemeney Lambertus A L M LALM de Wall Liesbeth L L LLL Heilmann Stefanie S Hofmann Aybike A Gehlen Jan J Schumacher Johannes J Szczepanska Maria M Taranta-Janusz Katarzyna K Kroll Pawel P Krzemien Grazyna G Szmigielska Agnieszka A Schreuder Michiel F MF Weber Stefanie S Zaniew Marcin M Roeleveld Nel N Reutter Heiko H Feitz Wout F J WFJ Hilger Alina C AC

Frontiers in pediatrics 20220927

Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotype ...[more]

PMID: 36238604

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Project description:ObjectiveTo construct reference values for fetal urinary bladder distension in pregnancy and use Z-scores as a diagnostic tool to differentiate posterior urethral valves (PUV) from urethral atresia (UA).MethodsThis was a prospective cross-sectional study in healthy singleton pregnancies aimed at constructing nomograms of fetal urinary bladder diameter and volume between 15 and 35 weeks' gestation. Z-scores of longitudinal bladder diameter (LBD) were calculated and validated in a cohort of fetuses with megacystis with ascertained postnatal or postmortem diagnosis, collected from a retrospective, multicenter study. Correlations between anatomopathological findings, based on medical examination of the infant or postmortem examination, and fetal megacystis were established. The accuracy of the Z-scores was evaluated by receiver-operating-characteristics (ROC)-curve analysis.ResultsNomograms of fetal urinary bladder diameter and volume were produced from three-dimensional ultrasound volumes in 225 pregnant women between 15 and 35 weeks of gestation. A total of 1238 urinary bladder measurements were obtained. Z-scores, derived from the fetal nomograms, were calculated in 106 cases with suspected lower urinary tract obstruction (LUTO), including 76 (72%) cases with PUV, 22 (21%) cases with UA, four (4%) cases with urethral stenosis and four (4%) cases with megacystis-microcolon-intestinal hypoperistalsis syndrome. Fetuses with PUV showed a significantly lower LBD Z-score compared to those with UA (3.95 vs 8.83, P < 0.01). On ROC-curve analysis, we identified 5.2 as the optimal Z-score cut-off to differentiate fetuses with PUV from the rest of the study population (area under the curve, 0.84 (95% CI, 0.748-0.936); P < 0.01; sensitivity, 74%; specificity, 86%).ConclusionsZ-scores of LBD can distinguish reliably fetuses with LUTO caused by PUV from those with other subtypes of LUTO, with an optimal cut-off of 5.2. This information should be useful for prenatal counseling and management of LUTO. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Project description:BackgroundPosterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development.ObjectiveTo identify genetic variants associated with kidney injury in patients with obstructive uropathy.Design setting and participantsWe included 487 patients born in 1981 or later who underwent pyeloplasty or valve resection before 18 yr of age in the discovery phase, 102 PUV patients in a first replication phase, and 102 in a second replication phase.Outcome measurements and statistical analysisSigns of kidney injury were defined as dialysis, nephrectomy, kidney transplantation, estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2, high blood pressure, antihypertensive medication use, proteinuria, and/or one kidney functioning at <45%. We used χ2 tests to calculate p values and odds ratios for >600 000 single-nucleotide polymorphisms (SNPs) in the discovery sample comparing patients with and without signs of kidney injury within 5 yr after surgery. We performed stratified analyses for PUV and UPJO and Kaplan-Meier and Cox regression analyses in the discovery and two replication samples for the associated SNPs, and RNA and protein expression analyses for the associated gene in fetal tissues.Results and limitationsDespite the small and nonhomogeneous sample, we observed suggestive associations for six SNPs in three loci, of which rs6874819 in the CDH12 gene was the most clear (p = 7.5 × 10-7). This SNP also seemed to be associated with time to kidney injury in the PUV discovery and replication samples. RNA expression analyses showed clear CDH12 expression in fetal kidneys, which was confirmed by protein immunolocalization.ConclusionsThis study identified CDH12 as a candidate gene for kidney injury in PUV.Patient summaryWe found that variants of the CDH12 gene increase the risk of kidney injury in patients with extra flaps of tissue in the urethra (posterior urethral valves). This is the first report on this gene in this context. Our study provides interesting new information about the pathways involved and important leads for further research for this condition.

Project description:Introduction: To obtain a successful renal transplant (RT) outcome in patients with posterior urethral valves (PUV), it is necessary to accomplish an adequate bladder dysfunction treatment. Our aim was to determine prognostic factors related to bladder dysfunction management in long-term RT outcome in patients with PUV. Methods: A retrospective review of patients with PUV who received a first RT after 1985 in our institution with at least 5 years of follow-up was performed. Variables analyzed included prenatal diagnosis, age of diagnosis, initial presentation and management, bladder dysfunction treatment, other surgical treatments, pre-transplant dialysis, age of transplantation, type of donor, immunosuppression regimen, vascular and urological complications, rejections episodes, and graft survival. Results: Fifty-one patients were included in the analysis. Prenatal diagnosis was done in 37.3%. Median age of diagnosis was 0.30 (0-88) months. Initial presentation was vesicoureteral reflux (VUR) in 78% and obstructive ureterohydronefrosis in 35.3%. Initial management was valve ablation (29.4%), pyelo-ureterostomy (64.7%), and vesicostomy (5.9%). In 33.3%, a type of bladder dysfunction treatment was performed: 21.6% bladder augmentation (BA), 15.7% Mitrofanoff procedure, 17.6% anticholinergic drugs, and 27.5% clean intermittent catheterization (CIC). Pre-transplant dialysis was received by 66.7%. Transplantation was performed at 6.28 ± 5.12 years, 62.7% were cadaveric and 37.3% living-donor grafts. Acute rejection episodes were found in 23.6%. Urological complications included recurrent urinary tract infections (UTIs) (31.4%); native kidneys VUR (31.4%); graft VUR (45.1%); and ureteral obstruction (2%). Vascular complications occurred in 3.9%. Mean graft survival was 11.1 ± 6.9 years. Analyzing the prognostic factor that influenced graft survival, patients with had CIC or a Mitrofanoff procedure had a significant better long-term graft survival after 10 years of follow-up (p < 0.05), despite of the existence of more recurrent UTIs in them. A better graft survival was also found in living-donor transplants (p < 0.05). No significant differences were observed in long-term graft survival regarding native kidneys or graft VUR, BA, immunosuppression regimen, or post-transplant UTIs. Conclusion: Optimal bladder dysfunction treatment, including CIC with or without a Mitrofanoff procedure, might result in better long-term graft survival in patients with PUV. These procedures were not related to a worse RT outcome in spite of being associated with more frequent UTIs.

Project description:ObjectivesTo identify the diagnostic performance of clinical and radiological signs (on voiding cystourethrography [VCUG]) to detect posterior urethral valves (PUV) in the post-neonatal period.Materials and methodsOne hundred eighteen males (median age = 0.8 years, range = 1 month-14 years, 48 toilet-trained) undergoing VCUG in a 2-year period were prospectively enrolled. Direct (dilated posterior urethra) and indirect (hypertrophied bladder neck, musculus interuretericus hypertrophy, and trabeculated appearance of the bladder wall) PUV signs on VCUG were assessed. Uroflowmetry was defined pathological by patterns suggesting infravesical obstruction.ResultsTwenty-two patients with direct, 28 with indirect PUV signs on VCUG, and one with normal VCUG but persisting micturition symptoms with pathological uroflowmetry underwent urethrocystoscopy and in 43/51 a PUV diagnosis was made (n = 22, 51.2%, with direct PUV signs). In 8/28 patients with indirect signs, PUV were not confirmed. Among non-toilet-trained patients, none of the clinical signs/symptoms was associated with PUV while among toilet-trained patients only pathological uroflowmetry (odds ratio, OR = 4.0 [95% confidence interval:1.2-13.2; p = 0.02]) and pathological uroflowmetry with history of urinary tract infection (OR = infinity) were significantly associated with PUV. Significant associations with PUV of direct and indirect signs on VCUG were found both in toilet-trained and non-toilet trained patients. Direct PUV sign had 100% specificity and sensitivity while indirect PUV signs showed sensitivity = 58.1% and specificity = 89.3%. The absence of any radiological sign had a negative predictive value = 98.5%.ConclusionOnly half of patients with endoscopy-confirmed PUV presents with direct sign of PUV on VCUG. Accounting for indirect PUV signs on VCUG and pathological uroflowmetry (in toilet-trained children) could improve the PUV detection rate.Clinical relevance statementIndirect radiological PUV signs should be valorized when interpreting VCUG to improve the PUV detection rate. The absence of any radiological PUV (direct and indirect) sign on VCUG excludes PUV with a very high negative predictive value.Key points• Worldwide agreement is that a non-dilated urethra on voiding cystourethrography excludes obstruction. • Half of patients with posterior urethral valves have non-dilated urethra on voiding cystourethrography. • Accounting for indirect signs of posterior urethral valves on voiding cystourethrography improves the diagnostic performance.

Dataset Information

Genome-wide association study in patients with posterior urethral valves.

Publications

Genome-wide association study in patients with posterior urethral valves.

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