Christina B Joseph1, Marta Mariniello2, Ayumi Yoshifuji2, Guglielmo Schiano2, Jennifer Lake2, Jonathan Marten1, Anne Richmond1, Jennifer E Huffman3,4, Archie Campbell5,6, Sarah E Harris7, Stephan Troyanov8, Massimiliano Cocca9, Antonietta Robino9, Sébastien Thériault10,11, Kai-Uwe Eckardt12,13, Matthias Wuttke14, Yurong Cheng14, Tanguy Corre15,16,17, Ivana Kolcic18, Corrinda Black19, Vanessa Bruat20, Maria Pina Concas9, Cinzia Sala21, Stefanie Aeschbacher22, Franz Schaefer23, Sven Bergmann16,17,24, Harry Campbell25, Matthias Olden26, Ozren Polasek18, David J Porteous5,6, Ian J Deary7, Francois Madore8, Philip Awadalla8, Giorgia Girotto9,27, Sheila Ulivi9, David Conen11, Elke Wuehl22, Eric Olinger2,28, James F Wilson1,25, Murielle Bochud15, Anna Köttgen14, Caroline Hayward29,5, Olivier Devuyst30. 1. Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom. 2. Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology Institute of Physiology, University of Zurich, Zurich, Switzerland. 3. Center for Population Genomics,VA Boston Healthcare System, Jamaica Plain, Massachusetts. 4. The Framingham Heart Study, Framingham, Massachusetts. 5. Centre for Genomic & Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom. 6. Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, United Kingdom. 7. Lothian Birth Cohorts, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom. 8. Division of Nephrology, Hôpital du Sacre-Coeur de Montreal, Montreal, Canada. 9. Institute for Maternal and Child Health IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) "Burlo Garofolo" 34127 Trieste, Italy. 10. Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Canada. 11. Population Health Research Institute, McMaster University, Hamilton, Canada. 12. Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany. 13. Department of Nephrology and Medical Intensive Care, Charite Universitätsmedizin Berlin, Berlin, Germany. 14. Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 15. Center for Primary Care and Public Health (Unisante), University of Lausanne, Lausanne, Switzerland. 16. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland. 17. Swiss Institute of Bioinformatics, Lausanne, Switzerland. 18. Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia. 19. Aberdeen Centre for Health Data Science, School of Medicine, Medical Science and Nutrition, University of Aberdeen, Aberdeen, United Kingdom. 20. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. 21. Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. 22. Cardiology Division, University Hospital Basel, Basel, Switzerland. 23. Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. 24. Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa. 25. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom. 26. Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany. 27. Department of Medicine, Surgery and Health Sciences, University of Trieste, 34149, Trieste, Italy. 28. Translational and Clinical Research Institute, Newcastle upon Tyne, Newcastle, United Kingdom. 29. Medical Research Council Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom olivier.devuyst@uzh.ch Caroline.Hayward@ed.ac.uk. 30. Mechanisms of Inherited Kidney Disorders Group, Institute of Physiology Institute of Physiology, University of Zurich, Zurich, Switzerland olivier.devuyst@uzh.ch Caroline.Hayward@ed.ac.uk.
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 (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 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 KRT40, WDR72, UMOD, and PDILT 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 UMOD-PDILT locus on kidney function.
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 (P 1.24E-08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E-88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 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 KRT40, WDR72, UMOD, and PDILT 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 UMOD-PDILT locus on kidney function.
Authors: Gonçalo R Abecasis; David Altshuler; Adam Auton; Lisa D Brooks; Richard M Durbin; Richard A Gibbs; Matt E Hurles; Gil A McVean Journal: Nature Date: 2010-10-28 Impact factor: 49.962
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