Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen
Authors: Salem Rany M. , Todd Jennifer N. , Sandholm Niina , Cole Joanne B. , Chen Wei-Min , Andrews Darrell , Pezzolesi Marcus G. , McKeigue Paul M. , Hiraki Linda T. , Qiu Chengxiang , Nair Viji , Di Liao Chen , Cao Jing Jing , Valo Erkka , Onengut-Gumuscu Suna , Smiles Adam M. , McGurnaghan Stuart J. , Haukka Jani K. , Harjutsalo Valma , Brennan Eoin P. , van Zuydam Natalie , Ahlqvist Emma , Doyle Ross , Ahluwalia Tarunveer S. , Lajer Maria , Hughes Maria F. , Park Jihwan , Skupien Jan , Spiliopoulou Athina , Liu Andrew , Menon Rajasree , Boustany-Kari Carine M. , Kang Hyun M. , Nelson Robert G. , Klein Ronald , Klein Barbara E. , Lee Kristine E. , Gao Xiaoyu , Mauer Michael , Maestroni Silvia , Caramori Maria Luiza , de Boer Ian H. , Miller Rachel G. , Guo Jingchuan , Boright Andrew P. , Tregouet David , Gyorgy Beata , Snell-Bergeon Janet K. , Maahs David M. , Bull Shelley B. , Canty Angelo J. , Palmer Colin N.A. , Stechemesser Lars , Paulweber Bernhard , Weitgasser Raimund , Sokolovska Jelizaveta , Rovīte Vita , Pīrāgs Valdis , Prakapiene Edita , Radzeviciene Lina , Verkauskiene Rasa , Panduru Nicolae Mircea , Groop Leif C. , McCarthy Mark I. , Gu Harvest F. , Möllsten Anna , Falhammar Henrik , Brismar Kerstin , Martin Finian , Rossing Peter , Costacou Tina , Zerbini Gianpaolo , Marre Michel , Hadjadj Samy , McKnight Amy J. , Forsblom Carol , McKay Gareth , Godson Catherine , Maxwell A. Peter , Kretzler Matthias , Susztak Katalin , Colhoun Helen M. , Krolewski Andrzej , Paterson Andrew D. , Groop Per-Henrik , Rich Stephen S. , Hirschhorn Joel N. , Florez Jose C. ,   SUMMIT Consortium, DCCT/EDIC Research Group, GENIE Consortium
Published: September 2019

Significance Statement
Although studies show that diabetic kidney disease has a heritable component, searches for the genetic determinants of this complication of diabetes have had limited success. In this study, a new international genomics consortium, the JDRF funded Diabetic Nephropathy Collaborative Research Initiative, assembled nearly 20,000 samples from participants with type 1 diabetes, with and without kidney disease. The authors found 16 new diabetic kidney disease–associated loci at genome-wide significance. The strongest signal centers on a protective missense coding variant at COL4A3, a gene that encodes a component of the glomerular basement membrane that, when mutated, causes the progressive inherited nephropathy Alport syndrome. These GWAS-identified risk loci may provide insights into the pathogenesis of diabetic kidney disease and help identify potential biologic targets for prevention and treatment.

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 genome-wide 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.