Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

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SUMMIT Consortium , DCCT EDIC Res Grp , GENIE Consortium , Salem , R M , Todd , J N , Sandholm , N , Valo , E , Haukka , J K , Harjutsalo , V , Groop , L C , Forsblom , C , Groop , P-H , Florez , J C & Panduru , N M 2019 , ' Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen ' , Journal of the American Society of Nephrology , vol. 30 , no. 10 , pp. 2000-2016 . https://doi.org/10.1681/ASN.2019030218

Title: Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen
Author: SUMMIT Consortium; DCCT EDIC Res Grp; GENIE Consortium; Salem, Rany M.; Todd, Jennifer N.; Sandholm, Niina; Valo, Erkka; Haukka, Jani K.; Harjutsalo, Valma; Groop, Leif C.; Forsblom, Carol; Groop, Per-Henrik; Florez, Jose C.; Panduru, Nicolae Mircea
Contributor: University of Helsinki, Medicum
University of Helsinki, HUS Abdominal Center
University of Helsinki, HUS Abdominal Center
University of Helsinki, Research Programs Unit
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Research Programs Unit
University of Helsinki, HUS Abdominal Center
University of Helsinki, HUS Abdominal Center
Date: 2019-10
Language: eng
Number of pages: 17
Belongs to series: Journal of the American Society of Nephrology
ISSN: 1046-6673
URI: http://hdl.handle.net/10138/307422
Abstract: 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.
Subject: RECEPTOR TYROSINE KINASES
COLLECTIN 11 CL-11
NITRIC-OXIDE
NEPHROPATHY
EXPRESSION
GENE
MUTATIONS
PROTEIN
SUSCEPTIBILITY
COMPLICATIONS
3111 Biomedicine
1184 Genetics, developmental biology, physiology
3121 General medicine, internal medicine and other clinical medicine
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