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Loci for insulin processing and secretion provide insight into type 2 diabetes risk.
Broadaway, K Alaine; Yin, Xianyong; Williamson, Alice; Parsons, Victoria A; Wilson, Emma P; Moxley, Anne H; Vadlamudi, Swarooparani; Varshney, Arushi; Jackson, Anne U; Ahuja, Vasudha; Bornstein, Stefan R; Corbin, Laura J; Delgado, Graciela E; Dwivedi, Om P; Fernandes Silva, Lilian; Frayling, Timothy M; Grallert, Harald; Gustafsson, Stefan; Hakaste, Liisa; Hammar, Ulf; Herder, Christian; Herrmann, Sandra; Højlund, Kurt; Hughes, David A; Kleber, Marcus E; Lindgren, Cecilia M; Liu, Ching-Ti; Luan, Jian'an; Malmberg, Anni; Moissl, Angela P; Morris, Andrew P; Perakakis, Nikolaos; Peters, Annette; Petrie, John R; Roden, Michael; Schwarz, Peter E H; Sharma, Sapna; Silveira, Angela; Strawbridge, Rona J; Tuomi, Tiinamaija; Wood, Andrew R; Wu, Peitao; Zethelius, Björn; Baldassarre, Damiano; Eriksson, Johan G; Fall, Tove; Florez, Jose C; Fritsche, Andreas; Gigante, Bruna; Hamsten, Anders.
Afiliação
  • Broadaway KA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • Yin X; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Williamson A; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Department of Clinical Biochemistry, University of Cambridge, Cambrid
  • Parsons VA; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • Wilson EP; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • Moxley AH; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • Vadlamudi S; Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
  • Varshney A; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Jackson AU; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
  • Ahuja V; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
  • Bornstein SR; Department of Internal Medicine, Metabolic and Vascular Medicine, MedicCal Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuher
  • Corbin LJ; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Delgado GE; Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
  • Dwivedi OP; University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland.
  • Fernandes Silva L; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
  • Frayling TM; College of Medicine and Health, Exeter University, Exeter, UK.
  • Grallert H; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neu
  • Gustafsson S; Department of Medical Sciences, Clinical Epidemiology, Uppsala University, Uppsala, Sweden.
  • Hakaste L; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
  • Hammar U; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Herder C; German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospita
  • Herrmann S; Department of Internal Medicine, Prevention and Care of Diabetes, Medical Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany.
  • Højlund K; Steno Diabetes Center Odense, Odense, Denmark.
  • Hughes DA; Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
  • Kleber ME; Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany; SYNLAB MVZ Humangenetik Mannheim, Mannheim, BW, Germany.
  • Lindgren CM; Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Nuffield Department of Population Health, University of Oxford, Oxford, UK; Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK; Broad Institute, Cambridge, MA, US
  • Liu CT; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Luan J; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, UK.
  • Malmberg A; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Moissl AP; Institute of Nutritional Sciences, Friedrich-Schiller-University, Jena, Germany; Competence Cluster for Nutrition and Cardiovascular Health, Halle-Jena-Leipzig, Germany; Medical Faculty Mannheim, Heidelberg University, Mannheim, BW, Germany.
  • Morris AP; Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, The University of Manchester, Manchester, UK.
  • Perakakis N; Department of Internal Medicine, Metabolic and Vascular Medicine, MedicCal Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuher
  • Peters A; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research, Neuherberg, Germany.
  • Petrie JR; School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
  • Roden M; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düssel
  • Schwarz PEH; Department of Internal Medicine, Prevention and Care of Diabetes, Medical Faculty Carl Gustav Carus, Dresden, Germany; Helmholtz Zentrum München, Paul Langerhans Institute Dresden, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; German Center for Diabetes Research, Neuherb
  • Sharma S; German Center for Diabetes Research, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neu
  • Silveira A; Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden; Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Strawbridge RJ; Institute of Health and Wellbeing, Mental Health and Wellbeing, University of Glasgow, Glasgow, UK; Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Tuomi T; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Abdominal Center, Endocrinology, Helsinki University Hospital, Helsinki, Finland.
  • Wood AR; Genetics of Complex Traits, College of Medicine and Health, University of Exeter, Exeter, UK.
  • Wu P; Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
  • Zethelius B; Department of Geriatrics, Uppsala University, Uppsala, Sweden.
  • Baldassarre D; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy; Cardiovascular Prevention Area, Centro Cardiologico Monzino I.R.C.C.S., Milan, Italy.
  • Eriksson JG; Department of General Practice and Primary Health Care, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland; Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore.
  • Fall T; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
  • Florez JC; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • Fritsche A; Department of Internal Medicine, Diabetology, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany; German Center for Diabetes Research, Neuherberg, Germany.
  • Gigante B; Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Hamsten A; Department of Medicine Solna, Division of Cardiovascular Medicine, Karolinska Institutet, Stockholm, Sweden.
Am J Hum Genet ; 110(2): 284-299, 2023 02 02.
Article em En | MEDLINE | ID: mdl-36693378
ABSTRACT
Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proinsulina / Diabetes Mellitus Tipo 2 Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proinsulina / Diabetes Mellitus Tipo 2 Tipo de estudo: Etiology_studies / Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Am J Hum Genet Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos