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J Am Soc Nephrol. 2017 Feb;28(2):557-574. doi: 10.1681/ASN.2016020231. Epub 2016 Sep 19.

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

Author information

1
Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
2
Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
3
Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
4
Wellcome Trust Centre for Human Genetics
5
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
6
Medical Research Institute
7
Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
8
Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom.
9
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
10
Department of Information Engineering, University of Padova, Padova, Italy.
11
Computational Sciences, Pfizer Worldwide Research and Development, Berlin, Germany.
12
Departments of Genetics
13
Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
14
Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts.
15
Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.
16
Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts.
17
Sorbonne Universities, Pierre et Marie Curie University (UPMC) and National Institute for Health and Medical Research, Mixed Research Unit in Health (UMR_S) 1166, Paris, France.
18
Institute for Cardiometabolism and Nutrition, Genomics and pathophysiology of Cardiovascular diseases, Paris, France.
19
Department of Paediatrics, Institute of Metabolic Science, and.
20
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom.
21
Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
22
Laboratory of Informatics and Systems Engineering for Clinical Research, Scientific Institute for Research, Hospitalization and Health Care, IRCCS (Instituto di Ricovero e Cura a Carattere Scientifico); Salvatore Maugeri Foundation, Pavia, Italy.
23
Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, United Kingdom.
24
Diabetic Complications, Steno Diabetes Center, Gentofte, Denmark.
25
The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
26
Centre for Vascular Prevention, Danube University Krems, Krems, Austria
27
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
28
Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
29
Cardiovascular and Metabolic Diseases Research Unit, and.
30
Computational Sciences, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
31
Department of Health, Aarhus University, Aarhus, Denmark.
32
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
33
Functional Research Unit of Medicine and Pharmacy, University of Poitiers, Poitiers, France.
34
Department of Endocrinology-Diabetology and Center of Clinical Investigation, Poitiers University Hospital, Poitiers, France.
35
Institute National pour la Santé et la Recherche Médicale, National Institute for Health and Medical Research, Center of Clinical Investigation 1402 and Unit 1082, Poitiers, France.
36
Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
37
Regional Nephrology Unit, Belfast City Hospital, Belfast, United Kingdom; and.
38
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
39
Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
40
Baker IDI (International Diabetes Institute) Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Abstract

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.

KEYWORDS:

diabetic kidney disease; genetics and development; genome-wide association study; whole exome sequencing

PMID:
27647854
PMCID:
PMC5280020
DOI:
10.1681/ASN.2016020231
[Indexed for MEDLINE]
Free PMC Article

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