A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
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- Natalie R. van Zuydam
- Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
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- Emma Ahlqvist
- Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
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- Harshal Deshmukh
- Newcastle University, Newcastle, U.K.
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- N. William Rayner
- Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
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- Moustafa Abdalla
- Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
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- Claes Ladenvall
- Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Daniel Ziemek
- Inflammation and Immunology Research Unit, Pfizer, Berlin, Germany
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- Eric Fauman
- Computational Target Validation, Pfizer, Cambridge, MA
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- Neil R. Robertson
- Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
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- Paul M. McKeigue
- Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, U.K.
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- Erkka Valo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
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- Carol Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
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- Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
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- Annalisa Perna
- Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy
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- Erica Rurali
- Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy
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- M. Loredana Marcovecchio
- Department of Paediatrics, University of Cambridge, Cambridge, U.K.
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- Robert P. Igo
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH
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- Rany M. Salem
- Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA
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- Norberto Perico
- Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy
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- Maria Lajer
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
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- Annemari Käräjämäki
- Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland
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- Minako Imamura
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
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- Michiaki Kubo
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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- Atsushi Takahashi
- Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Japan
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- Xueling Sim
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
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- Jianjun Liu
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
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- Rob M. van Dam
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
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- Guozhi Jiang
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Claudia H.T. Tam
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Andrea O.Y. Luk
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Heung Man Lee
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Cadmon K.P. Lim
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Cheuk Chun Szeto
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Wing Yee So
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Juliana C.N. Chan
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- Su Fen Ang
- Clinical Research Unit, Khoo Teck Puat Hospital, National Healthcare Group, Singapore
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- Rajkumar Dorajoo
- Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
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- Ling Wang
- Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
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- Tan Si Hua Clara
- Clinical Research Unit, Khoo Teck Puat Hospital, National Healthcare Group, Singapore
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- Amy-Jayne McKnight
- Centre for Public Health, Queen's University Belfast, Belfast, U.K.
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- Seamus Duffy
- Centre for Public Health, Queen's University Belfast, Belfast, U.K.
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- Marcus G. Pezzolesi
- Division of Nephrology and Hypertension and Diabetes & Metabolism Research Center, University of Utah Health, Salt Lake City, UT
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- Michel Marre
- Sorbonnes Université, University Pierre and Marie Curie, INSERM UMRS 1166, Institute for Cardiometabolism and Nutrition, Department of Genomics and Pathophysiology of Cardiovascular Diseases, Paris, France
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- Beata Gyorgy
- Sorbonnes Université, University Pierre and Marie Curie, INSERM UMRS 1166, Institute for Cardiometabolism and Nutrition, Department of Genomics and Pathophysiology of Cardiovascular Diseases, Paris, France
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- Samy Hadjadj
- Endocrinology-Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
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- Linda T. Hiraki
- Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Canada
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- Tarunveer S. Ahluwalia
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
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- Peter Almgren
- Diabetes and Cardiovascular Disease–Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Christina-Alexandra Schulz
- Diabetes and Cardiovascular Disease–Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Marju Orho-Melander
- Diabetes and Cardiovascular Disease–Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Allan Linneberg
- Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark
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- Cramer Christensen
- Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark
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- Daniel R. Witte
- Department of Public Health, Aarhus University, Aarhus, Denmark
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- Niels Grarup
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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- Ivan Brandslund
- Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
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- Olle Melander
- Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Andrew D. Paterson
- Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Canada
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- David Tregouet
- Sorbonnes Université, University Pierre and Marie Curie, INSERM UMRS 1166, Institute for Cardiometabolism and Nutrition, Department of Genomics and Pathophysiology of Cardiovascular Diseases, Paris, France
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- Alexander P. Maxwell
- Centre for Public Health, Queen's University Belfast, Belfast, U.K.
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- Su Chi Lim
- Diabetes Centre, Clinical Research Unit, Department of Medicine, Khoo Teck Puat Hospital, National Healthcare Group, Singapore
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- Ronald C.W. Ma
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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- E Shyong Tai
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore
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- Shiro Maeda
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
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- Valeriya Lyssenko
- Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Tiinamaija Tuomi
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
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- Andrzej S. Krolewski
- Joslin Diabetes Center, Harvard Medical School, Boston, MA
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- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA
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- Joel N. Hirschhorn
- Center for Basic and Translational Obesity Research and Division of Endocrinology, Boston Children's Hospital, Boston, MA
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- Jose C. Florez
- Programs in Medical and Population Genetics and Metabolism, Broad Institute, Cambridge, MA
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- David Dunger
- Department of Paediatrics, University of Cambridge, Cambridge, U.K.
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- Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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- Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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- Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
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- Giuseppe Remuzzi
- Clinical Research Center for Rare Diseases “Aldo e Cele Daccò,” Istituto di Ricerche Farmacologiche “Mario Negri,” Bergamo, Italy
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- Mary Julia Brosnan
- Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Pfizer, Cambridge, MA
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- Colin N.A. Palmer
- Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
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- Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
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- Helen M. Colhoun
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K.
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- Leif C. Groop
- Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden
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- Mark I. McCarthy
- Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
抄録
<jats:p>Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.</jats:p>
収録刊行物
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- Diabetes
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Diabetes 67 (7), 1414-1427, 2018-04-27
American Diabetes Association