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Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes

2015; American Diabetes Association; Volume: 65; Issue: 3 Linguagem: Inglês

10.2337/db15-1313

1939-327X

Alexander Teumer, Adrienne Tin, Rossella Sorice, Mathias Gorski, Nan Cher Yeo, Audrey Y. Chu, Man Li, Yong Li, Vladan Mijatovic, Yi-An Ko, Daniel Taliun, Alessandro Luciani, Ming‐Huei Chen, Qiong Yang, Meredith C. Foster, Matthias Olden, Linda T. Hiraki, Bamidele O. Tayo, Christian Fuchsberger, Aida Karina Dieffenbach, Alan R. Shuldiner, Albert V. Smith, Allison Zappa, Antonio Lupo, Barbara Kollerits, Bélen Ponte, Bénédicte Stengel, Bernhard K. Krämer, Bernhard Paulweber, Braxton D. Mitchell, Caroline Hayward, Catherine Helmer, Christa Meisinger, Christian Gieger, Christian M. Shaffer, Christian Müller, Claudia Langenberg, Daniel Ackermann, David S. Siscovick, Eric Boerwinkle, Florian Kronenberg, Georg Ehret, Georg Homuth, Gérard Waeber, Gerjan Navis, Giovanni Gambaro, Giovanni Malerba, Guðný Eiríksdóttir, Li Guo, H.-Erich Wichmann, Harald Grallert, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Holly Kramer, Irene Mateo Leach, Igor Rudan, Hans L. Hillege, J. Beckmann, Jean‐Charles Lambert, Jian’an Luan, Jing Zhao, John Chalmers, Josef Coresh, Joshua C. Denny, Katja Butterbach, Lenore J. Launer, Luigi Ferrucci, Lyudmyla Kedenko, Margot Haun, Marie Metzger, Mark Woodward, Matthew Hoffman, Matthias Nauck, Mélanie Waldenberger, Menno Pruijm, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nicholas J. Wareham, Nicole Endlich, Nicole Soranzo, Ozren Polašek, Pim van der Harst, Peter P. Pramstaller, Péter Vollenweider, Philipp S. Wild, Ron T. Gansevoort, Rainer Rettig, Reiner Biffar, Robert J. Carroll, Ronit Katz, Ruth J. F. Loos, Shih‐Jen Hwang, Stefan Coassin, Sven Bergmann, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanguy Corre, Tanja Zeller, Thomas Illig, Thor Aspelund, Toshiko Tanaka, Uwe Lendeckel, Uwe Völker, Vilmundur Guðnason, Vincent Chouraki, Wolfgang Köenig, Zoltán Kutalik, Jeffrey R. O’Connell, Afshin Parsa, Iris M. Heid, Andrew D. Paterson, Ian H. de Boer, Olivier Devuyst, Jozef Lazar, Karlhans Endlich, Katalin Suszták, Johanne Tremblay, Pavel Hamet, Howard J. Jacob, Carsten A. Böger, Caroline S. Fox, Cristian Pattaro, Anna Köttgen,

Liver Disease Diagnosis and Treatment

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.