Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes
Authors: Teumer Alexander , Tin Adrienne , Sorice Rossella , Gorski Mathias , Yeo Nan Cher , Chu Audrey Y. , Li Man , Li Yong , Mijatovic Vladan , Ko Yi-An , Taliun Daniel , Luciani Alessandro , Chen Ming-Huei , Yang Qiong , Foster Meredith C. , Olden Matthias , Hiraki Linda T. , Tayo Bamidele O. , Fuchsberger Christian , Dieffenbach Aida Karina , Shuldiner Alan R. , Smith Albert V. , Zappa Allison M. , Lupo Antonio , Kollerits Barbara , Ponte Belen , Stengel Bénédicte , Krämer Bernhard K. , Paulweber Bernhard , Mitchell Braxton D. , Hayward Caroline , Helmer Catherine , Meisinger Christa , Gieger Christian , Shaffer Christian M. , Müller Christian , Langenberg Claudia , Ackermann Daniel , Siscovick David ,   DCCT/EDIC, Boerwinkle Eric , Kronenberg Florian , Ehret Georg B. , Homuth Georg , Waeber Gerard , Navis Gerjan , Gambaro Giovanni , Malerba Giovanni , Eiriksdottir Gudny , Li Guo , Wichmann H. Erich , Grallert Harald , Wallaschofski Henri , Völzke Henry , Brenner Herrmann , Kramer Holly , Leach I. Mateo , Rudan Igor , Hillege Hans L. , Beckmann Jacques S. , Lambert Jean Charles , Luan Jian'an , Zhao Jing Hua , Chalmers John , Coresh Josef , Denny Joshua C. , Butterbach Katja , Launer Lenore J. , Ferrucci Luigi , Kedenko Lyudmyla , Haun Margot , Metzger Marie , Woodward Mark , Hoffman Matthew J. , Nauck Matthias , Waldenberger Melanie , Pruijm Menno , Bochud Murielle , Rheinberger Myriam , Verweij Niek , Wareham Nicholas J. , Endlich Nicole , Soranzo Nicole , Polasek Ozren , van der Harst Pim , Pramstaller Peter Paul , Vollenweider Peter , Wild Philipp S. , Gansevoort Ron T. , Rettig Rainer , Biffar Reiner , Carroll Robert J. , Katz Ronit , Loos Ruth J.F. , Hwang Shih-Jen , Coassin Stefan , Bergmann Sven , Rosas Sylvia E. , Stracke Sylvia , Harris Tamara B. , Corre Tanguy , Zeller Tanja , Illig Thomas , Aspelund Thor , Tanaka Toshiko , Lendeckel Uwe , Völker Uwe , Gudnason Vilmundur , Chouraki Vincent , Koenig Wolfgang , Kutalik Zoltan , O'Connell Jeffrey R. , Parsa Afshin , Heid Iris M. , Paterson Andrew D. , de Boer Ian H. , Devuyst Olivier , Lazar Jozef , Endlich Karlhans , Susztak Katalin , Tremblay Johanne , Hamet Pavel , Jacob Howard J. , Böger Carsten A. , Fox Caroline S. , Pattaro Cristian , Köttgen Anna 
Published: December 2015

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.