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

Abstract

BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo 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.ResultsOur 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).ConclusionsThe 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.

Single cell transcriptomics reveal disrupted kidney filter cell-cell interactions after early and selective podocyte injury

“…This result confirmed that individual gene data derived from the single cell transcriptomic experiment could be independently validated, with spatial resolution, bolstering the validity of the conclusions drawn by computational analyses. Furthermore, these data highlight that the key response to injury by a specific population of podocytes is to upregulate collagen production, which may account for the prominent or thick GBM observed in progressive diseases such as DKD (27).…”

“…One of the critical components of the GBM is collagen type IV 5 (Col4a5); mutations in this gene cause Alport syndrome and FSGS in humans (25,26). Variants in Col4a3, another structural component of the GBM, were recently identified by a comprehensive genome wide association study (GWAS) in diabetic kidney disease (DKD) (27).…”

Genetic Disorders of the Glomerular Filtration Barrier

“…Although the link between genetic variants encoding type IV collagen chains and rare kidney disease is well established, recent large genetic cohort studies suggest COL4A genes have a role in diseases that are much more common. Variants in COL4A genes have been found to be associated with CKD, diabetic nephropathy, cardiovascular disease, and stroke (38)(39)(40)(41)(42). This is perhaps representative of the organ-specific function of basement membranes and the role of the different type IV collagen isoforms.…”

Protective factors as biomarkers and targets for prevention and treatment of diabetic nephropathy: From current human evidence to future possibilities

“…As a member of the TGF-b family, BMP-7 was first speculated to be a pro-fibrotic factor, but recently an abundance of research presented a strong anti-fibrotic, anti-inflammatory and antiapoptotic effect. BMP-7 was identified as one of potential genes for DN in the most recent genome-wide association study in the Juvenile Diabetes Research Foundation Diabetic Nephropathy Collaborative Research Initiative, which has assembled 20,000 participants with type 1 diabetes, with and without DKD 37 . Earlier, a proteomic analysis carried in type 2 diabetes patients from the ADVANCE trial, showed a graded increase in the risk of CKD in individuals with lower circulating BMP-7 levels or significantly higher TGF-b1 levels 38 .…”