Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin.
David J Porteous, Kai-Uwe Eckardt, Matthias Wuttke, Yurong Cheng, Tanguy Corre, Corrinda Black, Vanessa Bruat, Maria Pina Concas, Cinzia Sala, Harry Campbell, Matthias Olden, Sébastien Thériault, Ian J Deary, Francois Madore, Philip Awadalla, Giorgia Girotto, Sheila Ulivi, Elke Wuehl, Eric Olinger, James F Wilson, Caroline Hayward, Olivier Devuyst, Guglielmo Schiano, Ivana Kolcic, Ozren Polašek, David Conen, Sven Bergmann, Franz Schaefer, Murielle Bochud, Stefanie Aeschbacher, Christina B Joseph, Marta Mariniello, Ayumi Yoshifuji, Anna Köttgen, Jennifer Lake, Jonathan Marten, Anne Richmond, Jennifer E Huffman, Archie Campbell, Sarah E Harris, Stephan Troyanov, Massimiliano Cocca, Antonietta Robino
Journal: Journal of the American Society of Nephrology : JASN
2022;33(3):511-529
PMID: 35228297
Abstract
BACKGROUND
Uromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.
METHODS
We conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.
RESULTS
Two genome-wide significant signals were identified for uUMOD: a novel locus ( 1.24E-08) over the gene coding for KRT40, a type 1 keratin expressed in the kidney, and the locus ( 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over and . Two genome-wide significant signals for uUCR were identified at the locus and at the novel locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion.
CONCLUSIONS
Common variants in , , , and associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the locus on kidney function.
Copyright © 2022 by the American Society of Nephrology.
Address:
Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom.; Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology Institute of Physiology, University of Zurich, Zurich, Switzerland.; Center for Population Genomics,VA Boston Healthcare System, Jamaica Plain, Massachusetts.; The Framingham Heart Study, Framingham, Massachusetts.; Centre for Genomic & Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.; Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom.; Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.; Division of Nephrology, Hôpital du Sacre-Coeur de Montreal, Montreal, Canada.; Institute for Maternal and Child Health IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) "Burlo Garofolo" 34127 Trieste, Italy.; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Canada.; Population Health Research Institute, McMaster University, Hamilton, Canada.; Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany.; Department of Nephrology and Medical Intensive Care, Charite Universitätsmedizin Berlin, Berlin, Germany.; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.; Center for Primary Care and Public Health (Unisante), University of Lausanne, Lausanne, Switzerland.; Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.; Swiss Institute of Bioinformatics, Lausanne, Switzerland.; Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.; Aberdeen Centre for Health Data Science, School of Medicine, Medical Science and Nutrition, University of Aberdeen, Aberdeen, United Kingdom.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.; Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Cardiology Division, University Hospital Basel, Basel, Switzerland.; Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.; Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.; Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom.; Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.; Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149, Trieste, Italy.; Translational and Clinical Research Institute, Newcastle upon Tyne, Newcastle, United Kingdom.
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