A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Natalie R van Zuydam; Emma Ahlqvist; Niina Sandholm; Harshal Deshmukh; N William Rayner; Moustafa Abdalla; Claes Ladenvall; Daniel Ziemek; Eric Fauman; Neil R Robertson; Paul M McKeigue; Erkka Valo; Carol Forsblom; Valma Harjutsalo; Finnish Diabetic Nephropathy Study (FinnDiane); Annalisa Perna; Erica Rurali; M Loredana Marcovecchio; Robert P Igo Jr; Rany M Salem; Norberto Perico; Maria Lajer; Annemari Käräjämäki; Minako Imamura; Michiaki Kubo; Atsushi Takahashi; Xueling Sim; Jianjun Liu; Rob M van Dam; Guozhi Jiang; Claudia H T Tam; Andrea O Y Luk; Heung Man Lee; Cadmon K P Lim; Cheuk Chun Szeto; Wing Yee So; Juliana C N Chan; Hong Kong Diabetes Registry Theme-based Research Scheme Project Group; Su Fen Ang; Rajkumar Dorajoo; Ling Wang; Tan Si Hua Clara; Amy-Jayne McKnight; Seamus Duffy; Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group; Marcus G Pezzolesi; GENIE (GEnetics of Nephropathy an International Effort) Consortium; Michel Marre; Beata Gyorgy; Samy Hadjadj; Linda T Hiraki; Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group; Tarunveer S Ahluwalia; Peter Almgren; Christina-Alexandra Schulz; Marju Orho-Melander; Allan Linneberg; Cramer Christensen; Daniel R Witte; Niels Grarup; Ivan Brandslund; Olle Melander; Andrew D Paterson; David Tregouet; Alexander P Maxwell; Su Chi Lim; Ronald C W Ma; E Shyong Tai; Shiro Maeda; Valeriya Lyssenko; Tiinamaija Tuomi; Andrzej S Krolewski; Stephen S Rich; Joel N Hirschhorn; Jose C Florez; David Dunger; Oluf Pedersen; Torben Hansen; Peter Rossing; Giuseppe Remuzzi; SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium; Mary Julia Brosnan; Colin N A Palmer; Per-Henrik Groop; Helen M Colhoun; Leif C Groop; Mark I McCarthy

doi:10.2337/db17-0914

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

Diabetes. 2018 Jul;67(7):1414-1427. doi: 10.2337/db17-0914. Epub 2018 Apr 27.

Authors

Natalie R van Zuydam^{1

2}, Emma Ahlqvist³, Niina Sandholm^{4

5

6}, Harshal Deshmukh⁷, N William Rayner^{8

2

9}, Moustafa Abdalla^{8

2

10}, Claes Ladenvall³, Daniel Ziemek¹¹, Eric Fauman¹², Neil R Robertson^{8

2}, Paul M McKeigue¹³, Erkka Valo^{4

5

6}, Carol Forsblom^{4

5

6}, Valma Harjutsalo^{4

5

6

14}; Finnish Diabetic Nephropathy Study (FinnDiane); Annalisa Perna¹⁵, Erica Rurali¹⁵, M Loredana Marcovecchio¹⁶, Robert P Igo Jr¹⁷, Rany M Salem¹⁸, Norberto Perico¹⁵, Maria Lajer¹⁹, Annemari Käräjämäki^{20

21}, Minako Imamura^{22

23

24}, Michiaki Kubo²⁴, Atsushi Takahashi^{25

26}, Xueling Sim²⁷, Jianjun Liu^{27

28

29}, Rob M van Dam²⁷, Guozhi Jiang³⁰, Claudia H T Tam³⁰, Andrea O Y Luk^{30

31

32}, Heung Man Lee^{30

31

32

33}, Cadmon K P Lim³⁰, Cheuk Chun Szeto³⁰, Wing Yee So³⁰, Juliana C N Chan^{30

31

32}; Hong Kong Diabetes Registry Theme-based Research Scheme Project Group; Su Fen Ang³⁴, Rajkumar Dorajoo²⁸, Ling Wang²⁸, Tan Si Hua Clara³⁴, Amy-Jayne McKnight³⁵, Seamus Duffy³⁵; Warren 3 and Genetics of Kidneys in Diabetes (GoKinD) Study Group; Marcus G Pezzolesi³⁶; GENIE (GEnetics of Nephropathy an International Effort) Consortium; Michel Marre³⁷, Beata Gyorgy³⁷, Samy Hadjadj^{38

39

40}, Linda T Hiraki⁴¹; Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group; Tarunveer S Ahluwalia^{19

42}, Peter Almgren⁴³, Christina-Alexandra Schulz⁴³, Marju Orho-Melander⁴³, Allan Linneberg^{44

45

46}, Cramer Christensen⁴⁷, Daniel R Witte^{48

49}, Niels Grarup⁴², Ivan Brandslund^{50

51}, Olle Melander⁵², Andrew D Paterson⁴¹, David Tregouet³⁷, Alexander P Maxwell³⁵, Su Chi Lim^{53

54

55}, Ronald C W Ma^{30

31

32

33}, E Shyong Tai^{27

54

56}, Shiro Maeda^{22

23

24}, Valeriya Lyssenko^{3

57}, Tiinamaija Tuomi^{4

6

58

59}, Andrzej S Krolewski⁶⁰, Stephen S Rich⁶¹, Joel N Hirschhorn^{62

63

64}, Jose C Florez^{63

65

66}, David Dunger^{16

67}, Oluf Pedersen⁴², Torben Hansen^{42

68}, Peter Rossing^{19

42}, Giuseppe Remuzzi^{15

69

70}; SUrrogate markers for Micro- and Macrovascular hard endpoints for Innovative diabetes Tools (SUMMIT) Consortium; Mary Julia Brosnan⁷¹, Colin N A Palmer⁷², Per-Henrik Groop^{4

5

6

73}, Helen M Colhoun⁷⁴, Leif C Groop^{3

59}, Mark I McCarthy^{8

2

75}

Collaborators

S Koivula, T Uggeldahl, T Forslund, A Halonen, A Koistinen, P Koskiaho, M Laukkanen, J Saltevo, M Tiihonen, M Forsen, H Granlund, A-C Jonsson, B Nyroos, P Kinnunen, A Orvola, T Salonen, A Vähänen, Kotka R Paldanius, M Riihelä, L Ryysy, Kemi H Laukkanen, P Nyländen, A Sademies, S Anderson, B Asplund, U Byskata, P Liedes, M Kuusela, T Virkkala, A Nikkola, E Ritola, Tapiola M Niska, H Saarinen, Samaria E Oukko-Ruponen, T Virtanen, Viherlaakso A Lyytinen, Puistola H Kari, T Simonen, Suutarila A Kaprio, J Kärkkäinen, B Rantaeskola, Toolo P Kääriäinen, J Haaga, A-L Pietiläinen, S Klemetti, T Nyandoto, E Rontu, S Satuli-Autere, Korso R Toivonen, H Virtanen Lansimaki, R Ahonen, M Ivaska-Suomela, A Jauhiainen, Martinlaakso M Laine, T Pellonpää, R Puranen, Myyrmaki A Airas, J Laakso, K Rautavaara, Rekola M Erola, E Jatkola, Tikkurila R Lönnblad, A Malm, J Mäkelä, E Rautamo, P Hentunen, J Lagerstam, M Feodoroff, D Gordin, O Heikkilä, K Hietala, J Fagerudd, M Korolainen, L Kyllönen, J Kytö, S Lindh, K Pettersson-Fernholm, M Rosengård-Bärlund, A Sandelin, L Thorn, J Tuomikangas, T Vesisenaho, J Wadén, V Sipilä, Forssa T Kalliomäki, J Koskelainen, R Nikkanen, N Savolainen, H Sulonen, E Valtonen, L Norvio, A Hämäläinen, E Toivanen, Jamsa A Parta, I Pirttiniemi, S Aranko, S Ervasti, R Kauppinen-Mäkelin, A Kuusisto, T Leppälä, K Nikkilä, L Pekkonen, Kajaani S Jokelainen, K Kananen, M Karjalainen, P Kemppainen, A-M Mankinen, A Reponen, M Sankari, P Suominen, A Lappalainen, M Liimatainen, J Santaholma, A Aimolahti, E Huovinen, V Ilkka, M Lehtimäki, E Pälikkö-Kontinen, A Vanhanen, E Koskinen, T Siitonen, E Huttunen, R Ikäheimo, P Karhapää, P Kekäläinen, M Laakso, T Lakka, E Lampainen, L Moilanen, S Tanskanen, L Niskanen, U Tuovinen, I Vauhkonen, E Voutilainen, Ronald C W Ma, Juliana C N Chan, Yu Huang, Hui-Yao Lan, Si Lok, Brian Tomlinson, Stephen K W Tsui, Weichuan Yu, Kevin Y L Yip, Ting Fung Chan, Xiaodan Fan, Wing Yee So, Cheuk Chun Szeto, Nelson Tang, Andrea O Luk, Xiaoyu Tian, Guozhi Jiang, Claudia H T Tam, Heung Man Lee, Cadmon K P Lim, Katie K H Chan, Fangying Xie, Alex C W Ng, Grace P Y Cheung, Ming-Wai Yeung, Shi Mai, Fei Xie, Sen Zhang, Pu Yu, Meng Weng, A P Maxwell, A J McKnight, D A Savage, J Walker, S Thomas, G C Viberti, A J M Boulton, S Marshall, A G Demaine, B A Millward, S C Bain, Niina Sandholm, Carol Forsblom, Valma Harjutsalo, Ville-Petteri Mäkinen, Aila J Ahola, Emma Dahlström, Daniel Gordin, Outi Heikkilä, Kustaa Hietala, Janne Kytö, Markku Lehto, Raija Lithovius, Nicolae Mircea Panduru, Maija Parkkonen, Milla Rosengård-Bärlund, Markku Saraheimo, Jenny Söderlund, Aino Soro-Paavonen, Anna Syreeni, Lena M Thorn, Nina Tolonen, Johan Wadén, Per-Henrik Groop, Amy Jayne McKnight, Gareth J McKay, Alexander P Maxwell, Rany M Salem, Tamara Isakova, Cameron Palmer, Candace Guiducci, Andrew Taylor, Daniel B Mirel, Winfred W Williams, Joel N Hirschhorn, Jose C Florez, Eoin P Brennan, Denise M Sadlier, Finian Martin, Catherine Godson, Lynne Mayer, Rose Gubitosi-Klug, Patti Bourne, Mark Schutta, Mary Ellen Lackaye, Naina Sinha Gregory, Davida Kruger, J Kimberly Jones, Arti Bhan, Ellen Golden, Lloyd Aiello, Mary Larkin, David Nathan, Georgia Ziegler, Susan Caulder, Clare Pittman, Louis Luttrell, Maria Lopes-Virella, Mary Johnson, Kimberly Gunyou, Richard Bergenstal, Brenda Vittetoe, William Sivitz, Nancy Flaherty, John Bantle, Susan Hitt, David Goldstein, Dean Hainsworth, Lori Cimino, Trevor Orchard, Christine Wigley, Samuel Dagogo-Jack, Suzanne Strowig, Philip Raskin, Annette Barnie, Bernard Zinman, Robyn Fahlstrom, Jerry Palmer, Judith Harth, Marsha Driscoll, Charlotte McDonald, Janie Lipps Hagan, Michael May, Lucy Levandoski, Neil White, Patricia Gatcomb, William Tamborlane, Daphne Adelman, Susan Colson, Mark Molitch, Gayle Lorenzi, Sunder Mudaliar, Sherry Johnsonbaugh, Ryan Miller, Janene Canady, David Schade, Maria Luisa Bernal, John Malone, Anthony Morrison, Catherine Martin, William Herman, Rodica Pop-Busui, Catherine Cowie, Ellen Leschek, Patricia Cleary, John Lachin, Bernie Zinman, Gayle Lorenzi, Barbara Braffett, Mike Steffes, Valerie Arends, Barbara Blodi, Ronald Danis, Daniel Lawrence, Hugh Wabers, Elsayed Soliman, Zhu-Ming Zhang, Charles Campbell, Susan Hensley, Lisa Keasler, Michael Mark, Markus Albertini, Carine Boustany, Alexander Ehlgen, Martin Gerl, Jochen Huber, Corinna Schölch, Heike Zimdahl-Gelling, Leif Groop, Elisabet Agardh, Emma Ahlqvist, Tord Ajanki, Nibal Al Maghrabi, Peter Almgren, Jan Apelqvist, Eva Bengtsson, Lisa Berglund, Harry Björckbacka, Ulrika Blom-Nilsson, Mattias Borell, Agneta Burström, Corrado Cilio, Magnus Cinthio, Karl Dreja, Pontus Dunér, Daniel Engelbertsen, Joao Fadista, Maria Gomez, Isabel Goncalves, Bo Hedblad, Anna Hultgårdh, Martin E Johansson, Cecilia Kennbäck, Jasmina Kravic, Claes Ladenvall, Åke Lernmark, Eero Lindholm, Charlotte Ling, Holger Luthman, Olle Melander, Malin Neptin, Jan Nilsson, Peter Nilsson, Tobias Nilsson, Gunilla Nordin, Marju Orho-Melander, Emilia Ottoson-Laakso, Annie Persson, Margaretha Persson, Mats-Åke Persson, Jacqueline Postma, Elisabeth Pranter, Sara Rattik, Gunnar Sterner, Lilian Tindberg, Maria Wigren, Anna Zetterqvist, Mikael Åkerlund, Gerd Ostling, Timo Kanninen, Anni Ahonen-Bishopp, Anita Eliasson, Timo Herrala, Paivi Tikka-Kleemola, Anders Hamsten, Christer Betsholtz, Ami Björkholm, Fariba Foroogh, Guillem Genové, Karl Gertow, Bruna Gigante, Bing He, Karin Leander, Olga McLeod, Maria Nastase-Mannila, Jaako Patrakka, Angela Silveira, Rona Strawbridge, Karl Tryggvason, Max Vikström, John Ohrvik, Anne-May Österholm, Barbara Thorand, Christian Gieger, Harald Grallert, Tonia Ludwig, Barbara Nitz, Andrea Schneider, Rui Wang-Sattler, Astrid Zierer, Giuseppe Remuzzi, Ariela Benigni, Roberta Donadelli, Maria Domenica Lesti, Marina Noris, Norberto Perico, Annalisa Perna, Rossella Piras, Piero Ruggenenti, Erica Rurali, David Dunger, Ludo Chassin, Neil Dalton, John Deanfield, Jane Horsford, Clare Rice, James Rudd, Neil Walker, Karen Whitehead, Max Wong, Helen Colhoun, Fiona Adams, Tahira Akbar, Jill Belch, Harshal Deshmukh, Fiona Dove, Angela Ellingford, Bassam Farran, Mike Ferguson, Gary Henderson, Graeme Houston, Faisel Khan, Graham Leese, Yiyuan Liu, Shona Livingstone, Helen Looker, Margaret McCann, Stuart McGurnaghan, Andrew Morris, David Newton, Colin Palmer, Ewan Pearson, Gillian Reekie, Natalie Smith, Angela Shore, Kuni Aizawa, Claire Ball, Nick Bellenger, Francesco Casanova, Tim Frayling, Phil Gates, Kim Gooding, Andrew Hattersley, Roland Ling, David Mawson, Robin Shandas, David Strain, Clare Thorn, Ulf Smith, Ann Hammarstedt, Hans Häring, Oluf Pedersen, Georgio Sesti, Per-Henrik Groop, Emma Fagerholm, Carol Forsblom, Valma Harjutsalo, Maikki Parkkonen, Niina Sandholm, Nina Tolonen, Iiro Toppila, Erkka Valo, Veikko Salomaa, Aki Havulinna, Kati Kristiansson, Pia Okamo, Tomi Peltola, Markus Perola, Arto Pietilä, Samuli Ripatti, Marketta Taimi, Seppo Ylä-Herttuala, Mohan Babu, Marike Dijkstra, Erika Gurzeler, Jenni Huusko, Ivana Kholová, Markku Laakso, Mari Merentie, Marja Poikolainen, Mark McCarthy, Chris Groves, Thorhildur Juliusdottir, Fredrik Karpe, Vasiliki Lagou, Andrew Morris, Will Rayner, Neil Robertson, Natalie van Zuydam, Claudio Cobelli, Barbara Di Camillo, Francesca Finotello, Francesco Sambo, Gianna Toffolo, Emanuele Trifoglio, Riccardo Bellazzi, Nicola Barbarini, Mauro Bucalo, Christiana Larizza, Paolo Magni, Alberto Malovini, Simone Marini, Francesca Mulas, Silvana Quaglini, Lucia Sacchi, Francesca Vitali, Ele Ferrannini, Beatrice Boldrini, Michaela Kozakova, Andrea Mari, Carmela Morizzo, Lucrecia Mota, Andrea Natali, Carlo Palombo, Elena Venturi, Mark Walker, Carlo Patrono, Francesca Pagliaccia, Bianca Rocca, Pirjo Nuutila, Johanna Haukkala, Juhani Knuuti, Anne Roivainen, Antti Saraste, Paul McKeague, Marco Colombo, Birgit Steckel-Hamann, Krister Bokvist, Sudha Shankar, Melissa Thomas, Li-Ming Gan, Suvi Heinonen, Ann-Cathrine Jönsson-Rylander, Remi Momo, Volker Schnecke, Robert Unwin, Anna Walentinsson, Carl Whatling, Everson Nogoceke, Gonzalo Durán Pacheco, Ivan Formentini, Thomas Schindler, Piero Tortoli, Luca Bassi, Enrico Boni, Alessandro Dallai, Francesco Guidi, Matteo Lenge, Riccardo Matera, Alessandro Ramalli, Stefano Ricci, Jacopo Viti, Bernd Jablonka, Dan Crowther, Johan Gassenhuber, Sibylle Hess, Thomas Hubschle, Hans-Paul Juretschke, Hartmut Rutten, Thorsten Sadowski, Paulus Wohlfart, Julia Brosnan, Valerie Clerin, Eric Fauman, Craig Hyde, Anders Malarstig, Nick Pullen, Mera Tilley, Theresa Tuthill, Ciara Vangjeli, Daniel Ziemek

Affiliations

¹ Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K. nvanzuy@well.ox.ac.uk.
² Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.
³ Diabetes and Endocrinology, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁴ Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
⁵ Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁶ Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
⁷ Newcastle University, Newcastle, U.K.
⁸ Wellcome Centre Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K.
⁹ Human Genetics Programme, Wellcome Sanger Institute, University of Cambridge, Cambridge, U.K.
¹⁰ Department of Statistics, University of Oxford, Oxford, U.K.
¹¹ Inflammation and Immunology Research Unit, Pfizer, Berlin, Germany.
¹² Computational Target Validation, Pfizer, Cambridge, MA.
¹³ Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, U.K.
¹⁴ Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
¹⁵ Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," Istituto di Ricerche Farmacologiche "Mario Negri," Bergamo, Italy.
¹⁶ Department of Paediatrics, University of Cambridge, Cambridge, U.K.
¹⁷ Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH.
¹⁸ Department of Family Medicine and Public Health, University of California, San Diego, San Diego, CA.
¹⁹ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
²⁰ Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland.
²¹ Diabetes Center, Vaasa Health Care Center, Vaasa, Finland.
²² Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
²³ Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.
²⁴ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁵ Department of Genomic Medicine, National Cerebral and Cardiovascular Center, Suita, Japan.
²⁶ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
²⁷ Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
²⁸ Division of Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore.
²⁹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁰ Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
³¹ Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
³² Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.
³³ Integrated Bioinformatics Laboratory for Cancer and Metabolic Diseases, The Chinese University of Hong Kong, Hong Kong, China.
³⁴ Clinical Research Unit, Khoo Teck Puat Hospital, National Healthcare Group, Singapore.
³⁵ Centre for Public Health, Queen's University Belfast, Belfast, U.K.
³⁶ Division of Nephrology and Hypertension and Diabetes & Metabolism Research Center, University of Utah Health, Salt Lake City, UT.
³⁷ 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.
³⁸ Endocrinology-Diabetology, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
³⁹ Clinical Investigation Center 1402 and U1082, INSERM, University of Poitiers, Poitiers, France.
⁴⁰ Faculté de Médecine et de Pharmacie, University of Poitiers, Poitiers, France.
⁴¹ Genetics & Genome Biology, The Hospital for Sick Children, Toronto, Canada.
⁴² The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴³ Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁴⁴ Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark.
⁴⁵ Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark.
⁴⁶ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁴⁷ Department of Internal Medicine and Endocrinology, Vejle Hospital, Vejle, Denmark.
⁴⁸ Department of Public Health, Aarhus University, Aarhus, Denmark.
⁴⁹ Danish Diabetes Academy, Odense, Denmark.
⁵⁰ Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.
⁵¹ Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark.
⁵² Hypertension and Cardiovascular Disease, Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁵³ Diabetes Centre, Clinical Research Unit, Department of Medicine, Khoo Teck Puat Hospital, National Healthcare Group, Singapore.
⁵⁴ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵⁵ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁵⁶ Cardiovascular & Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore.
⁵⁷ KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Norway.
⁵⁸ Abdominal Center Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁵⁹ Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
⁶⁰ Joslin Diabetes Center, Harvard Medical School, Boston, MA.
⁶¹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
⁶² Center for Basic and Translational Obesity Research and Division of Endocrinology, Boston Children's Hospital, Boston, MA.
⁶³ Programs in Medical and Population Genetics and Metabolism, Broad Institute, Cambridge, MA.
⁶⁴ Department of Genetics, Harvard Medical School, Boston, MA.
⁶⁵ Diabetes Clinical Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.
⁶⁶ Department of Medicine, Harvard Medical School, Boston, MA.
⁶⁷ Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, U.K.
⁶⁸ Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
⁶⁹ Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.
⁷⁰ Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
⁷¹ Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Pfizer, Cambridge, MA.
⁷² Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, U.K.
⁷³ Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
⁷⁴ Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, U.K.
⁷⁵ National Institute for Health Research, Oxford Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, U.K.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Case-Control Studies
Diabetes Mellitus, Type 2 / complications*
Diabetes Mellitus, Type 2 / epidemiology
Diabetes Mellitus, Type 2 / genetics*
Diabetic Nephropathies / epidemiology
Diabetic Nephropathies / genetics*
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Kidney Failure, Chronic / complications
Kidney Failure, Chronic / epidemiology
Kidney Failure, Chronic / genetics
Male
Middle Aged
Polymorphism, Single Nucleotide
Renal Insufficiency, Chronic / complications
Renal Insufficiency, Chronic / epidemiology
Renal Insufficiency, Chronic / genetics

Abstract

Publication types

MeSH terms

Grants and funding