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

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 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

Diabetes 2016 Mar 2;65(3):803-17. Epub 2015 Dec 2.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Renal Division, Medical Center, University of Freiburg, Freiburg, Germany

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.

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http://diabetes.diabetesjournals.org/content/early/2015/11/2
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http://diabetes.diabetesjournals.org/lookup/doi/10.2337/db15
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http://dx.doi.org/10.2337/db15-1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764151PMC
March 2016
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