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The Genetic Landscape of Renal Complications in Type 1 Diabetes.
Sandholm, Niina; Van Zuydam, Natalie; Ahlqvist, Emma; Juliusdottir, Thorhildur; Deshmukh, Harshal A; Rayner, N William; Di Camillo, Barbara; Forsblom, Carol; Fadista, Joao; Ziemek, Daniel; Salem, Rany M; Hiraki, Linda T; Pezzolesi, Marcus; Trégouët, David; Dahlström, Emma; Valo, Erkka; Oskolkov, Nikolay; Ladenvall, Claes; Marcovecchio, M Loredana; Cooper, Jason; Sambo, Francesco; Malovini, Alberto; Manfrini, Marco; McKnight, Amy Jayne; Lajer, Maria; Harjutsalo, Valma; Gordin, Daniel; Parkkonen, Maija; Tuomilehto, Jaakko; Lyssenko, Valeriya; McKeigue, Paul M; Rich, Stephen S; Brosnan, Mary Julia; Fauman, Eric; Bellazzi, Riccardo; Rossing, Peter; Hadjadj, Samy; Krolewski, Andrzej; Paterson, Andrew D; Florez, Jose C; Hirschhorn, Joel N; Maxwell, Alexander P; Dunger, David; Cobelli, Claudio; Colhoun, Helen M; Groop, Leif; McCarthy, Mark I; Groop, Per-Henrik.
Afiliação
  • Sandholm N; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
  • Van Zuydam N; Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • Ahlqvist E; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
  • Juliusdottir T; Wellcome Trust Centre for Human Genetics
  • Deshmukh HA; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
  • Rayner NW; Medical Research Institute
  • Di Camillo B; Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
  • Forsblom C; Wellcome Trust Centre for Human Genetics
  • Fadista J; Division of Population Health Sciences, University of Dundee, Dundee, United Kingdom.
  • Ziemek D; Wellcome Trust Centre for Human Genetics
  • Salem RM; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.
  • Hiraki LT; Human Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
  • Pezzolesi M; Department of Information Engineering, University of Padova, Padova, Italy.
  • Trégouët D; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
  • Dahlström E; Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • Valo E; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
  • Oskolkov N; Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
  • Ladenvall C; Computational Sciences, Pfizer Worldwide Research and Development, Berlin, Germany.
  • Marcovecchio ML; Departments of Genetics
  • Cooper J; Programs in Metabolism and Medical and Population Genetics, Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts.
  • Sambo F; Divisions of Endocrinology and Genetics, Boston Children's Hospital, Boston, Massachusetts.
  • Malovini A; Genetics and Genome Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada.
  • Manfrini M; Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston, Massachusetts.
  • McKnight AJ; 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.
  • Lajer M; Institute for Cardiometabolism and Nutrition, Genomics and pathophysiology of Cardiovascular diseases, Paris, France.
  • Harjutsalo V; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
  • Gordin D; Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • Parkkonen M; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
  • Tuomilehto J; Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • Lyssenko V; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
  • McKeigue PM; Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
  • Rich SS; Department of Clinical Sciences, Diabetes and Endocrinology, Skåne University Hospital, Lund University, Malmö, Sweden.
  • Brosnan MJ; Department of Paediatrics, Institute of Metabolic Science, and.
  • Fauman E; Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom.
  • Bellazzi R; Department of Information Engineering, University of Padova, Padova, Italy.
  • Rossing P; Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy.
  • Hadjadj S; 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.
  • Krolewski A; Department of Information Engineering, University of Padova, Padova, Italy.
  • Paterson AD; Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, United Kingdom.
  • Florez JC; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
  • Hirschhorn JN; Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • Maxwell AP; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
  • Dunger D; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
  • Cobelli C; Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • Colhoun HM; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
  • Groop L; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.
  • McCarthy MI; Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
  • Groop PH; Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
J Am Soc Nephrol ; 28(2): 557-574, 2017 02.
Article em En | MEDLINE | ID: mdl-27647854
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Tipo 1 / Nefropatias Diabéticas Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Diabetes Mellitus Tipo 1 / Nefropatias Diabéticas Tipo de estudo: Prognostic_studies Limite: Adolescent / Adult / Female / Humans / Male / Middle aged Idioma: En Ano de publicação: 2017 Tipo de documento: Article