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.
Bibliographical noteFunding Information:
Dr. Onengut-Gumuscu reports grants from JDRF, during the conduct of the study. Dr. Caramori reports grants from Bayer Pharmaceuticals, personal fees from Elcelix, outside the submitted work. Dr. de Boer reports personal fees from Boehringer-Ingelheim, personal fees from Ironwood, non-financial support from Medtronic, non-financial support from Abbott, outside the submitted work. Dr. Snell-Bergeon reports grants from NIH, grants from JDRF, during the conduct of the study; other from GlaxoSmithKline, outside the submitted work. Dr. Weitgasser reports personal fees from Abbott, personal fees from Astra Zeneca, personal fees from Boehringer-Ingelheim, grants and personal fees from Eli Lilly, personal fees from MSD, grants and personal fees from NovoNordisk, personal fees from Dexcom, personal fees from Roche, grants and personal fees from Sanofi, personal fees from Servier, personal fees from Takeda, personal fees from Spar, outside the submitted work. Dr. McCarthy reports grants, personal fees and other from Pfizer, grants, personal fees and other from Merck, grants, personal fees and other from Novo Nordisk, grants from Takeda, grants from Servier, grants from Sanofi Aventis, grants from Boehringer Ingelheim, grants from Astra Zeneca, grants from Janssen, grants, personal fees and other from Eli Lilly, grants from Abb-vie, grants from Roche, during the conduct of the study; grants, personal fees and other from Pfizer, grants, personal fees and other from Eli Lilly, grants, personal fees and other from Merck, other from Zoe Global, other from Gen-entech (wef June 2019), outside the submitted work. Dr. Costacou reports grants from National Institutes of Health (NIH), during the conduct of the study. Dr. McKnight reports grants from Northern Ireland Public Health Agency (Research and Development Division) and Medical Research Council as part of the USA-Ireland-Northern Ireland research partnership and Department for the Economy NI 15/IA/3152 during the conduct of the study. Dr. Kretzler reports grants from NIH, non-financial support from University of Michigan, during the conduct of the study; grants from JDRF, grants from Astra-Zeneca, grants from NovoNordisc, grants from Eli Lilly, grants from Gilead, grants from Goldfinch Bio, grants from Merck, grants from Janssen, grants from Boehringer-Ingelheim, grants from Elpidera, grants from European Union Innovative Medicine Innitiative, outside the submitted work; In addition, Dr. Kretzler has a patent Biomarkers for CKD progression issued. Dr. Susztak reports grants from GSK, Regeneron, Boehringer, Gilead, Bayer, Lilly, Merck, outside the submitted work. Dr. Colhoun reports grants from AStraZeneca LP, other from Bayer, grants and other from Eli Lilly and Company, other from Novartis Pharmaceuticals, grants and other from Regeneron, grants from Pfizer Inc., other from Roche Pharmaceuticals, grants and other from Sanofi Aventis, grants and personal fees from Novo Nordisk, outside the submitted work. Dr. Groop reports personal fees from AbbVie, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Elo Water, personal fees from Janssen, personal fees from Medscape, personal fees from Mundipharma, personal fees from MSD, personal fees from Novartis, personal fees from Novo Nordisk, personal fees from Sanofi, outside the submitted work. Dr. Marre reports personal fees from Novo-Nordisk, personal fees from Servier, personal fees from Merck, outside the submitted work; and Marre is president of the Fon-dation Francophone pour la Recherche sur le Diabète, a French, non for profit institution. This institution is supported financially by the following companies: Novo-Nordisk, Merck, Sanofi, Eli Lilly, Astra-Zeneca, Roche, Abbott. Dr. Hirschhorn reports other from Camp4 Therapeutics, outside the submitted work. Dr. Florez reports personal fees from Janssen, outside the submitted work. Dr. Hiraki reports grants from Juvenile Diabetes Research Foundation (JDRF), during the conduct of the study. Dr. Rossing reports grants and other from Astra Zeneca, other from Boehringer Ingelheim, other from Bayer, grants and other from Novo Nordisk, other from MSD, other from Eli Lilly, other from astellas, other from Abbvie, other from Mundi Pharma, other from Sanofi, other from Gilead, outside the submitted work.
We acknowledge the following conflicts of interest: Groop has received investigator-initiated research grants from Eli Lilly and Roche, is an advisory board member for AbbVie, AstraZeneca, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi, and has received lecture fees from AstraZeneca, Boehringer In-gelheim, Eli Lilly, Elo Water, Genzyme, Merck Sharp & Dohme, Medscape, Novo Nordisk and Sanofi. McCarthy is a Wellcome Investigator and an NIHR Senior Investigator. He serves on advisory panels for Pfizer, NovoNordisk, and Zoe Global, has received honoraria from Merck, Pfizer, NovoNordisk and Eli Lilly, has stock options in Zoe Global, and has received research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier and Takeda. Rossing has received consultancy and/or speaking fees (to his institution) from AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Novo Nordisk and Sanofi Aventis and research grants from As-traZeneca and Novo Nordisk, and shares in Novo Nordisk.
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.
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