期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 30, 期 10, 页码 2000-2016出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2019030218
关键词
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资金
- JDRF [17-2013-7, 3-APF-2014-111-A-N, 2-SRA-2014-276-Q-R]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK081923, R01 DK105154]
- National Heart, Lung and Blood Institute [R00 HL122515]
- NIDDK [K12-DK094721, DK34818]
- European Foundation for the Study of Diabetes (EFSD)
- Academy of Finland [299200, 275614, 316664, 263401, 267882]
- Science Foundation Ireland - Health Research Board (SFI-HRB) US Ireland [SFI15/US/B3130]
- NIDDK
- Folkhalsan Research Foundation
- Wilhelm and Else Stockmann Foundation
- Liv och Halsa Foundation
- Helsinki University Central Hospital Research Funds (EVO)
- Novo Nordisk Foundation [NNF OC0013659]
- Rossi Memorial Fund
- National Eye Institute [EY016379]
- Family Erling-Persson foundation
- Stig and Gunborg Westman foundation
- Innovative Medicines Initiative (IMI) [SUMMIT 115006]
- Wellcome Trust [098381, 090532, 106310, 072960/Z/03/Z, 084726/Z/08/Z, 084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z]
- National Institutes of Health [R01-MH101814]
- Swedish Research Council
- European Research Council Advanced (ERC-Adv) [269045-GENE TARGET T2D]
- Sigrid JUselius Foundation
- NIH/NIDDK [2P30-DK-081943]
- European Union
- MRC [MC_PC_15025] Funding Source: UKRI
- Wellcome Trust [084726/Z/08/Z] Funding Source: Wellcome Trust
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.
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