@article{690f457574384c91ba09a579ee6ec81c,
title = "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 × 10210). 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 × 1027). 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.",
keywords = "Genome-Wide, Genetic Loci, Albuminuria, Diabetes",
author = "{4Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group} and Alexander Teumer and Adrienne Tin and Rossella Sorice and Mathias Gorski and Yeo, {Nan Cher} and Chu, {Audrey Y.} and Man Li and Yong Li and Vladan Mijatovic and Ko, {Yi An} and Daniel Taliun and Alessandro Luciani and Chen, {Ming Huei} and Qiong Yang and Foster, {Meredith C.} and Matthias Olden and Hiraki, {Linda T.} and Tayo, {Bamidele O.} and Christian Fuchsberger and Dieffenbach, {Aida Karina} and Shuldiner, {Alan R.} and Smith, {Albert V.} and Zappa, {Allison M.} and Antonio Lupo and Barbara Kollerits and Belen Ponte and B{\'e}n{\'e}dicte Stengel and Kr{\"a}mer, {Bernhard K.} and Bernhard Paulweber and Mitchell, {Braxton D.} and Caroline Hayward and Catherine Helmer and Christa Meisinger and Christian Gieger and Shaffer, {Christian M.} and Christian M{\"u}ller and Claudia Langenberg and Daniel Ackermann and David Siscovick and Eric Boerwinkle and Florian Kronenberg and Ehret, {Georg B.} and Georg Homuth and Gerard Waeber and Gerjan Navis and Giovanni Gambaro and Giovanni Malerba and Gudny Eiriksdottir and Guo Li and Wichmann, {H. Erich} and Harald Grallert and Henri Wallaschofski and Henry V{\"o}lzke and Herrmann Brenner and Holly Kramer and Leach, {I. Mateo} and Igor Rudan and Hillege, {Hans L.} and Beckmann, {Jacques S.} and Lambert, {Jean Charles} and Jian'an Luan and Zhao, {Jing Hua} and John Chalmers and Josef Coresh and Denny, {Joshua C.} and Katja Butterbach and Launer, {Lenore J.} and Luigi Ferrucci and Lyudmyla Kedenko and Margot Haun and Marie Metzger and Mark Woodward and Hoffman, {Matthew J.} and Matthias Nauck and Melanie Waldenberger and Menno Pruijm and Murielle Bochud and Myriam Rheinberger and Niek Verweij and Wareham, {Nicholas J.} and Nicole Endlich and Nicole Soranzo and Ozren Polasek and {Van Der Harst}, Pim and Pramstaller, {Peter Paul} and Peter Vollenweider and Wild, {Philipp S.} and Gansevoort, {Ron T.} and Rainer Rettig and Reiner Biffar and Carroll, {Robert J.} and Ronit Katz and Loos, {Ruth J.F.} and Hwang, {Shih Jen} and Stefan Coassin and Sven Bergmann and Rosas, {Sylvia E.} and Sylvia Stracke and Harris, {Tamara B.} and Tanguy Corre and Tanja Zeller and Thomas Illig and Thor Aspelund and Toshiko Tanaka and Uwe Lendeckel and Uwe V{\"o}lker and Vilmundur Gudnason and Vincent Chouraki and Wolfgang Koenig and Zoltan Kutalik and O'Connell, {Jeffrey R.} and Afshin Parsa and Heid, {Iris M.} and Paterson, {Andrew D.} and {De Boer}, {Ian H.} and Olivier Devuyst and Jozef Lazar and Karlhans Endlich and Katalin Susztak and Johanne Tremblay and Pavel Hamet and Jacob, {Howard J.} and B{\"o}ger, {Carsten A.} and Fox, {Caroline S.} and Cristian Pattaro and Anna K{\"o}ttgen",
year = "2016",
month = mar,
doi = "10.2337/db15-1313",
language = "English",
volume = "65",
pages = "803--817",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "3",
}
