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

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.

SUBMITTER: Salem RM

PROVIDER: S-EPMC6779358 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Salem Rany M RM Todd Jennifer N JN Sandholm Niina N Cole Joanne B JB Chen Wei-Min WM Andrews Darrell D Pezzolesi Marcus G MG McKeigue Paul M PM Hiraki Linda T LT Qiu Chengxiang C Nair Viji V Di Liao Chen C Cao Jing Jing JJ Valo Erkka E Onengut-Gumuscu Suna S Smiles Adam M AM McGurnaghan Stuart J SJ Haukka Jani K JK Harjutsalo Valma V Brennan Eoin P EP van Zuydam Natalie N Ahlqvist Emma E Doyle Ross R Ahluwalia Tarunveer S TS Lajer Maria M Hughes Maria F MF Park Jihwan J Skupien Jan J Spiliopoulou Athina A Liu Andrew A Menon Rajasree R Boustany-Kari Carine M CM Kang Hyun M HM Nelson Robert G RG Klein Ronald R Klein Barbara E BE Lee Kristine E KE Gao Xiaoyu X Mauer Michael M Maestroni Silvia S Caramori Maria Luiza ML de Boer Ian H IH Miller Rachel G RG Guo Jingchuan J Boright Andrew P AP Tregouet David D Gyorgy Beata B Snell-Bergeon Janet K JK Maahs David M DM Bull Shelley B SB Canty Angelo J AJ Palmer Colin N A CNA Stechemesser Lars L Paulweber Bernhard B Weitgasser Raimund R Sokolovska Jelizaveta J Rovīte Vita V Pīrāgs Valdis V Prakapiene Edita E Radzeviciene Lina L Verkauskiene Rasa R Panduru Nicolae Mircea NM Groop Leif C LC McCarthy Mark I MI Gu Harvest F HF Möllsten Anna A Falhammar Henrik H Brismar Kerstin K Martin Finian F Rossing Peter P Costacou Tina T Zerbini Gianpaolo G Marre Michel M Hadjadj Samy S McKnight Amy J AJ Forsblom Carol C McKay Gareth G Godson Catherine C Maxwell A Peter AP Kretzler Matthias M Susztak Katalin K Colhoun Helen M HM Krolewski Andrzej A Paterson Andrew D AD Groop Per-Henrik PH Rich Stephen S SS Hirschhorn Joel N JN Florez Jose C JC

Journal of the American Society of Nephrology : JASN 20190919 10

<h4>Background</h4>Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.<h4>Methods</h4>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 ...[more]

PMID: 31537649

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Project description:BackgroundCD151 is a cell-surface molecule of the tetraspanin family. Its lateral interaction with laminin-binding integrin ɑ3β1 is important for podocyte adhesion to the glomerular basement membrane (GBM). Deletion of Cd151 in mice induces glomerular dysfunction, with proteinuria and associated focal glomerulosclerosis, disorganisation of GBM and tubular cystic dilation. Despite this, CD151 is not routinely screened for in patients with nephrotic-range proteinuria. We aimed to better understand the relevance of CD151 in human kidney disease.MethodsNext-generation sequencing (NGS) was used to detect the variant in CD151. Electron and light microscopy were used to visualise the filtration barrier in the patient kidney biopsy, and immunoreactivity of patient red blood cells to anti-CD151/MER2 antibodies was performed. Further validation of the CD151 variant as disease-causing was performed in zebrafish using CRISPR-Cas9.ResultsWe report a young child with nail dystrophy and persistent urinary tract infections who was incidentally found to have nephrotic-range proteinuria. Through targeted NGS, a novel, homozygous truncating variant was identified in CD151, a gene rarely reported in patients with nephrotic syndrome. Electron microscopy imaging of patient kidney tissue showed thickening of GBM and podocyte effacement. Immunofluorescence of patient kidney tissue demonstrated that CD151 was significantly reduced, and we did not detect immunoreactivity to CD151/MER2 on patient red blood cells. CRISPR-Cas9 depletion of cd151 in zebrafish caused proteinuria, which was rescued by injection of wild-type CD151 mRNA, but not CD151 mRNA containing the variant sequence.ConclusionsOur results indicate that a novel variant in CD151 is associated with nephrotic-range proteinuria and microscopic haematuria and provides further evidence for a role of CD151 in glomerular disease. Our work highlights a functional testing pipeline for future analysis of patient genetic variants. A higher resolution version of the Graphical abstract is available as Supplementary information.

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

Publications

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

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