Genome-Wide association study of diabetic kidney disease highlights biology involved in glomerular basement membrane collagen

Rany M. Salem, Jennifer N. Todd, Niina Sandholm, Joanne B. Cole, Wei Min Chen, Darrell Andrews, Marcus G. Pezzolesi, Paul M.Keigue Mc, Linda T. Hiraki, Chengxiang Qiu, Viji Nair, Chen Di Liao, Jing Jing Cao, Erkka Valo, Suna Onengut-Gumuscu, Adam M. Smiles, Stuart J. Gurnaghan, Jani K. Haukka, Valma Harjutsalo, Eoin P. BrennanNatalie Van Zuydam, Emma Ahlqvist, Ross Doyle, Tarunveer S. Ahluwalia, Maria Lajer, Maria F. Hughes, Jihwan Park, Jan Skupien, Athina Spiliopoulou, Andrew Liu, Rajasree Menon, Carine M.Kari Boustany, Hyun M. Kang, Robert G. Nelson, Ronald Klein, Barbara E. Klein, Kristine E. Lee, Xiaoyu Gao, Michael Mauer, Silvia Maestroni, Maria Luiza Caramori, Ian H.De Boer Caramori, Rachel G. Miller, Jingchuan Guo, Andrew P. Boright, David Tregouet, Beata Gyorgy, Janet K.Bergeon Snell, David M. Maahs, Shelley B. Bull, Angelo J. Canty, Colin N.A. Palmer, Lars Stechemesser, Bernhard Paulweber, Raimund Weitgasser, Jelizaveta Sokolovska, Vita Rovite, Valdis Pyrags, Edita Prakapiene, Lina Radzeviciene, Rasa Verkauskiene, Nicolae Mircea Panduru, Leif C. Groop, Mark I.Carthy Mc, Harvest F. Gu, Anna Möllsten, Henrik Falhammar, Kerstin Brismar, Finian Martin, Peter Rossing, Tina Costacou, Gianpaolo Zerbini, Michel Marre, Samy Hadjadj, Amy J. Knight, Carol Forsblom, Gareth McKay, Catherine Godson, A. Peter Maxwell, Matthias Kretzler, Katalin Susztak, Helen M. Colhoun, Andrzej Krolewski, Andrew D. Paterson, Per Henrik Groop, Stephen S. Rich, Joel N. Hirschhorn, Jose C. Florez

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87 Scopus citations


Background Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. Methods To identify genetic variants predisposing to diabetic kidney disease, we performed genomewide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. Results Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). Conclusions The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

Original languageEnglish (US)
Pages (from-to)2000-2016
Number of pages17
JournalJournal of the American Society of Nephrology
Issue number10
StatePublished - 2019

Bibliographical note

Funding Information:
This study was supported by a grant from the JDRF (17-2013-7) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01 DK081923 and R01 DK105154. Salem was supported in part by JDRF grant 3-APF-2014-111-A-N, and National Heart, Lung and Blood Institute grant R00 HL122515. Todd was supported by NIDDK grant K12-DK094721. Sandholm received funds from the European Foundation for the Study of Diabetes (EFSD) Young Investigator Research Award funds and Academy of Finland (299200). Godson, Andrews, Brennan, Martin, Hughes, and Doyle are supported by Science Foundation Ireland - Health Research Board (SFI-HRB) US Ireland Research Partnership SFI15/US/B3130. Nelson was supported in part by the Intramural Research Program of the NIDDK. The FinnDiane study was funded by JDRF (17-2013-7), Folkhälsan Research Foundation, the Wilhelm and Else Stockmann Foundation, the Liv och Hälsa Foundation, Helsinki University Central Hospital Research Funds (EVO), the Novo Nordisk Foundation (NNF OC0013659), and Academy of Finland (275614 and 316664). The Pittsburgh Epidemiology of Diabetes Complications Study (EDC) study was supported by NIDDK grant DK34818 and by the Rossi Memorial Fund. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) study was funded by National Eye Institute grant EY016379. The Sweden study was supported by Family Erling-Persson (Brismar) and Stig and Gunborg Westman foundations (Gu). SUMMIT Consortium: this work was supported by Innovative Medicines Initiative (IMI) (SUMMIT 115006); Wellcome Trust grants 098381, 090532, and 106310; National Institutes of Health grant R01-MH101814; and JDRF grant 2-SRA-2014-276-Q-R; and other grants from Swedish Research Council, European Research Council Advanced (ERC-Adv) research grant 269045-GENE TARGET T2D, Academy of Finland grants 263401 and 267882, and Sigrid JUselius Foundation. The George M. O’Brien Michigan Kidney Translational Core Center, funded by NIH/NIDDK grant 2P30-DK-081943 for the bioinfor-matics support. The Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) was funded by the Wellcome Trust (072960/Z/ 03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z) and as part of the European Union’s IMI-SUMMIT program.

Publisher Copyright:
© 2019 American Society of Nephrology. All rights reserved.


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