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

DCCT/EDIC, 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 FuchsbergerAida 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, Igor Rudan, Ozren Polasek

Research output: Contribution to journalArticlepeer-review

Abstract

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with 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 mellitus 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. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated 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 vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.

Original languageEnglish
JournalDiabetes
DOIs
Publication statusPublished - 2 Dec 2015

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