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

Abstract

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.

• Authors: 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 M Zappa, Antonio Lupo, Barbara Kollerits, Belen 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 Siscovick, DCCT/EDIC, Eric Boerwinkle, Florian Kronenberg, Georg B Ehret, Georg Homuth, Gerard Waeber, Gerjan Navis, Giovanni Gambaro, Giovanni Malerba, Gudny Eiriksdottir, Guo Li, H Erich Wichmann, Harald Grallert, Henri Wallaschofski, Henry Völzke, Herrmann Brenner, Holly Kramer, I Mateo Leach, Igor Rudan, Hans L Hillege, Jacques S Beckmann, Jean Charles Lambert, Jian'an Luan, Jing Hua Zhao, John Chalmers, Josef Coresh, Joshua C Denny, Katja Butterbach, Lenore J Launer, Luigi Ferrucci, Lyudmyla Kedenko, Margot Haun, Marie Metzger, Mark Woodward, Matthew J Hoffman, Matthias Nauck, Melanie Waldenberger, Menno Pruijm, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nicholas J Wareham, Nicole Endlich, Nicole Soranzo, Ozren Polasek, Pim van der Harst, Peter Paul Pramstaller, Peter 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 Gudnason, Vincent Chouraki, Wolfgang Koenig, Zoltan Kutalik, Jeffrey R O'Connell, Afshin Parsa, Iris M Heid, Andrew D Paterson, Ian H de Boer, Olivier Devuyst, Jozef Lazar, Karlhans Endlich, Katalin Susztak, Johanne Tremblay, Pavel Hamet, Howard J Jacob, Carsten A Böger, Caroline S Fox, Cristian Pattaro, Anna Köttgen
• Journal: Diabetes (Diabetes) Vol. 65 Issue 3 Pg. 803-17 (Mar 2016) ISSN: 1939-327X [Electronic] United States
• PMID: 26631737 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Receptors, Cell Surface
• intrinsic factor-cobalamin receptor
• Sulfotransferases
• heparan sulfate 6-O-sulfotransferase
• CTSC protein, human
• Cathepsin C
• RAB38 protein, human
• Rab38 protein, rat
• rab GTP-Binding Proteins

Topics

• Adult
• Aged
• Albuminuria (etiology, genetics)
• Animals
• Cathepsin C (genetics)
• Diabetes Mellitus, Experimental
• Diabetes Mellitus, Type 2 (complications, genetics)
• Diabetic Nephropathies (etiology, genetics)
• Female
• Gene Knockout Techniques
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Kidney (metabolism)
• Kidney Tubules (metabolism)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Rats
• Receptors, Cell Surface (genetics)
• Sulfotransferases (genetics)
• rab GTP-Binding Proteins (genetics, metabolism)