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J Am Soc Nephrol DOI:10.1681/ASN.2019030218

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

Publication TypeJournal Article
Year of Publication2019
AuthorsSalem, RM, Todd, JN, Sandholm, N, Cole, JB, Chen, W-M, Andrews, D, Pezzolesi, MG, McKeigue, PM, Hiraki, LT, Qiu, C, Nair, V, Di Liao, C, Cao, JJing, Valo, E, Onengut-Gumuscu, S, Smiles, AM, McGurnaghan, SJ, Haukka, JK, Harjutsalo, V, Brennan, EP, Van Zuydam, N, Ahlqvist, E, Doyle, R, Ahluwalia, TS, Lajer, M, Hughes, MF, Park, J, Skupien, J, Spiliopoulou, A, Liu, A, Menon, R, Boustany-Kari, CM, Kang, HM, Nelson, RG, Klein, R, Klein, BE, Lee, KE, Gao, X, Mauer, M, Maestroni, S, Caramori, MLuiza, de Boer, IH, Miller, RG, Guo, J, Boright, AP, Trégouët, D, Gyorgy, B, Snell-Bergeon, JK, Maahs, DM, Bull, SB, Canty, AJ, Palmer, CNA, Stechemesser, L, Paulweber, B, Weitgasser, R, Sokolovska, J, Rovīte, V, Pirags, V, Prakapiene, E, Radzeviciene, L, Verkauskiene, R, Panduru, NMircea, Groop, LC, McCarthy, MI, Gu, HF, Möllsten, A, Falhammar, H, Brismar, K, Martin, F, Rossing, P, Costacou, T, Zerbini, G, Marre, M, Hadjadj, S, McKnight, AJ, Forsblom, C, McKay, G, Godson, C, A Maxwell, P, Kretzler, M, Susztak, K, Colhoun, HM, Krolewski, A, Paterson, AD, Groop, P-H, Rich, SS, Hirschhorn, JN, Florez, JC
Corporate AuthorsSUMMIT Consortium, DCCT/EDIC Research Group, GENIE Consortium
JournalJ Am Soc Nephrol
Date Published2019 Sep 19
ISSN1533-3450
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 ( gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in 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 ( or renal biology ( and ).

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.

DOI10.1681/ASN.2019030218
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31537649?dopt=Abstract

Alternate JournalJ. Am. Soc. Nephrol.
PubMed ID31537649