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Genome-wide association study of diabetic kidney disease highlights biology involved in renal basement membrane collagen

By Rany M. Salem, Jennifer N Todd, Niina Sandholm, Joanne Cole, Wei-Min Chen, Darrel Andrews, Marcus G Pezzolesi, Paul M McKeigue, Linda T Hiraki, Chengxiang Qiu, Viji Nair, Chen Di Liao, Jing Jing Cao, Erkka Valo, Suna Onengut-Gumuscu, Adam M Smiles, Stuart J. McGurnaghan, Jani K Haukka, Valma Harjutsalo, Eoin P. Brennan, Natalie 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 Boustany-Kari, Hyun M Kang, Robert G Nelson, Ronald Klein, Barbara E Klein, Kristine E Lee, Xiaoyu Gao, Michael Mauer, Silvia Maeastroni, Maria Luiza Caramori, Ian H. de Boer, Rachel G Miller, Jingchuan Guo, Andrew P Boright, David Tregouet, Beata Gyorgy, Janet K Snell-Bergeon, David M Maahs, Shelley B Bull, Angelo J. Canty, Colin N.A. Palmer, Lars Stechemesser, Bernhard Paulweber, Raimund Weitgasser, Jelizaveta Sokolovska, Vita Rovīte, Valdis Pīrāgs, Edita Prakapiene, Lina Radzeviciene, Rasa Verkauskiene, Nicolae Mircea Panduru, Leif C Groop, Mark I McCarthy, Harvest F Gu, Anna Möllsten, Henrik Falhammar, Kerstin Brismar, GENIE Consortium, DCCT/EDIC Research Group, SUMMIT Consortium, Finian Martin, Peter Rossing, Tina Costacou, Gianpaolo Zerbini, Michel Marre, Samy Hadjadj, Amy J McKnight, Carol Forsblom, Gareth McKay, C 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

Posted 19 Dec 2018
bioRxiv DOI: 10.1101/499616

Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions based on albuminuria and renal function. We identified 16 genome-wide significant 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) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology (COLEC11 and DDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential biological targets for prevention and treatment.

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