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J Am Soc Nephrol. 2019 Oct;30(10):2000-2016. doi: 10.1681/ASN.2019030218. Epub 2019 Sep 19.

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

Author information

1
Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California.
2
Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.
3
Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts.
4
Center for Genomic Medicine and.
5
Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.
6
Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
7
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine and.
8
Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, Virginia.
9
Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland.
10
Division of Nephrology and Hypertension, Diabetes and Metabolism Center, University of Utah, Salt Lake City, Utah.
11
Usher Institute of Population Health Sciences and Informatics and.
12
The Hospital for Sick Children, Toronto, Ontario, Canada.
13
Departments of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.
14
Division of Nephrology, Department of Internal Medicine and.
15
Joslin Diabetes Center, Boston, Massachusetts.
16
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
17
The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
18
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
19
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
20
Department of Genomics, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden.
21
Steno Diabetes Center Copenhagen, Gentofte, Denmark.
22
Department of Biostatistics and.
23
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
24
Cardiometabolic Diseases Research, Boehringer Ingelheim, Ridgefield, Connecticut.
25
Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, Michigan.
26
Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona.
27
University of Wisconsin-Madison, Madison, Wisconsin.
28
The George Washington University, Washington, DC.
29
University of Minnesota, Minneapolis, Minnesota.
30
Complications of Diabetes Unit, Division of Immunology, Transplantation and Infectious Diseases, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milano, Italy.
31
University of Washington, Seattle, Washington.
32
University of Pittsburgh Public Health, Pittsburgh, Pennsylvania.
33
INSERM UMR_S 1166, Sorbonne Université, UPMC Univ Paris 06, Paris, France.
34
ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
35
University of Colorado School of Medicine, Aurora, Colorado.
36
Department of Pediatrics-Endocrinology, Stanford University, Stanford, California.
37
The Lunenfeld-Tanenbaum Research Institute, University of Toronto, Toronto, Ontario, Canada.
38
Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada.
39
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
40
First Department of Medicine, Paracelsus Medical University, Salzburg, Austria.
41
Department of Medicine, Diakonissen-Wehrle Hospital, Salzburg, Austria.
42
University of Latvia, Riga, Latvia.
43
Latvian Biomedical Research and Study Centre, Riga, Latvia.
44
Pauls Stradins University Hospital, Riga, Latvia.
45
Medical Academy and.
46
Institute of Endocrinology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania.
47
2nd Clinical Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
48
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
49
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
50
Genentech, 1 DNA Way, South San Francisco, California.
51
Department of Clinical Science, Intervention and Technology and.
52
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
53
Division of Pediatrics, Department of Clinical Sciences, Umeå University, Umeå, Sweden.
54
Department of Molecular Medicine and Surgery, Rolf Luft Center for Diabetes Research and Endocrinology, Karolinska Institutet, Stockholm, Sweden.
55
Department of Endocrinology, Diabetes and Metabolism, Karolinska University Hospital, Stockholm, Sweden.
56
University of Copenhagen, Copenhagen, Denmark.
57
Department of Diabetology, Endocrinology and Nutrition, Bichat Hospital, DHU FIRE, Assistance Publique-Hôpitaux de Paris, Paris, France.
58
UFR de Médecine, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
59
INSERM UMRS 1138, Cordeliers Research Center, Paris, France.
60
Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.
61
Department of Endocrinology and Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
62
INSERM CIC 1402, Poitiers, France.
63
L'institut du thorax, INSERM, CNRS, CHU Nantes, Nantes, France.
64
Centre for Public Health, Queens University of Belfast, Northern Ireland, UK.
65
Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia; and.
66
Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; jcflorez@mgh.harvard.edu.
67
Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts.
68
Department of Medicine, Harvard Medical School, Boston, Massachusetts.

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.

KEYWORDS:

diabetes; diabetic nephropathy; end-stage renal disease; genetic renal disease; human genetics; kidney disease

PMID:
31537649
DOI:
10.1681/ASN.2019030218

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