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Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen
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2019 (English)In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 30, no 10, p. 2000-2016Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society of Nephrology , 2019. Vol. 30, no 10, p. 2000-2016
National Category
Urology and Nephrology Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-165367DOI: 10.1681/ASN.2019030218ISI: 000493453400022PubMedID: 31537649OAI: oai:DiVA.org:umu-165367DiVA, id: diva2:1372111
Funder
NIH (National Institute of Health)Novo Nordisk, NNF OC0013659Wellcome trust, 098381Wellcome trust, 090532Wellcome trust, 106310Wellcome trustWellcome trust, 084726/Z/08/ZWellcome trust, 084727/Z/08/ZWellcome trust, 085475/Z/08/ZWellcome trust, 085475/B/08/ZSwedish Research CouncilAvailable from: 2019-11-22 Created: 2019-11-22 Last updated: 2019-11-22Bibliographically approved

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Möllsten, Anna

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Cole, Joanne B.Valo, ErkkaMcGurnaghan, Stuart J.Brennan, Eoin P.Palmer, Colin N. A.Möllsten, Anna
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