CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases: A Genome-wide Association Study Among Patients with Obstructive Uropathies

Loes F M van der Zanden; Iris A L M van Rooij; Josine S L T Quaedackers; Rien J M Nijman; Martijn Steffens; Liesbeth L L de Wall; Ernie M H F Bongers; Franz Schaefer; Marietta Kirchner; Rouven Behnisch; Aysun K Bayazit; Salim Caliskan; Lukasz Obrycki; Giovanni Montini; Ali Duzova; Matthias Wuttke; Rachel Jennings; Neil A Hanley; Natalie J Milmoe; Paul J D Winyard; Kirsten Y Renkema; Michiel F Schreuder; Nel Roeleveld; Wout F J Feitz

doi:10.1016/j.euros.2021.04.001

CDH12 as a Candidate Gene for Kidney Injury in Posterior Urethral Valve Cases: A Genome-wide Association Study Among Patients with Obstructive Uropathies

Eur Urol Open Sci. 2021 Apr 24:28:26-35. doi: 10.1016/j.euros.2021.04.001. eCollection 2021 Jun.

Authors

Loes F M van der Zanden¹, Iris A L M van Rooij¹, Josine S L T Quaedackers², Rien J M Nijman², Martijn Steffens³, Liesbeth L L de Wall⁴, Ernie M H F Bongers⁵, Franz Schaefer⁶, Marietta Kirchner⁷, Rouven Behnisch⁷, Aysun K Bayazit⁸, Salim Caliskan⁹, Lukasz Obrycki¹⁰, Giovanni Montini^{11

12}, Ali Duzova¹³, Matthias Wuttke¹⁴, Rachel Jennings^{15

16}, Neil A Hanley^{15

16}, Natalie J Milmoe¹⁷, Paul J D Winyard¹⁷, Kirsten Y Renkema¹⁸, Michiel F Schreuder¹⁹, Nel Roeleveld¹, Wout F J Feitz⁴

Affiliations

¹ Radboud Institute for Health Sciences, Department for Health Evidence, Radboud university medical center, Nijmegen, The Netherlands.
² Department of Urology, University Medical Center Groningen, Groningen, The Netherlands.
³ Department of Urology, Isala, Zwolle, The Netherlands.
⁴ Radboud Institute for Molecular Life Sciences, Division of Pediatric Urology, Department of Urology, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands.
⁵ Radboud Institute for Molecular Life Sciences, Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.
⁶ Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
⁷ Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
⁸ Department of Pediatric Nephrology, Faculty of Medicine, Cukurova University, Adana, Turkey.
⁹ Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Istanbul, Turkey.
¹⁰ Department of Nephrology, Kidney Transplantation and Hypertension, Children's Memorial Health Institute, Warsaw, Poland.
¹¹ Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico di Milano, Milan, Italy.
¹² Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
¹³ Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
¹⁴ Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
¹⁵ Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
¹⁶ Endocrinology Department, Manchester University NHS Foundation Trust, Manchester, UK.
¹⁷ Nephro-Urology Research Group, Developmental Biology and Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
¹⁸ Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
¹⁹ Radboud Institute for Molecular Life Sciences, Department of Pediatric Nephrology, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands.

Abstract

Background: Posterior urethral valves (PUVs) and ureteropelvic junction obstruction (UPJO) are congenital obstructive uropathies that may impair kidney development.

Objective: To identify genetic variants associated with kidney injury in patients with obstructive uropathy.

Design setting and participants: We 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 analysis: Signs 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 limitations: Despite 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.

Conclusions: This study identified CDH12 as a candidate gene for kidney injury in PUV.

Patient summary: We 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.

Keywords: CDH12; Genome-wide association study; Obstructive uropathy; Posterior urethral valves.