A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants (original) (raw)
Genetics/Genomes/Proteomics/Metabolomics| May 10 2017
1Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K.
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2Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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3Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
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4Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
5Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA
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6Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
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7Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC
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8Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ
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9Max Planck Institute for Biology of Ageing, Cologne, Germany
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1Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K.
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10Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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10Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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11Department of Biological Psychology, VU University, Amsterdam, the Netherlands
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11Department of Biological Psychology, VU University, Amsterdam, the Netherlands
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12Diabetes Center, Internal Medicine Unit, VU University Medical Center, Amsterdam, the Netherlands
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13Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine IV, University of Tübingen, Tübingen, Germany
14Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich, University of Tübingen, Tübingen, Germany
15German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
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12Diabetes Center, Internal Medicine Unit, VU University Medical Center, Amsterdam, the Netherlands
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16EMGO+ Institute for Health and Care Research, VU University Medical Center, Department of General Practice, Amsterdam, the Netherlands
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12Diabetes Center, Internal Medicine Unit, VU University Medical Center, Amsterdam, the Netherlands
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17Department of Internal Medicine, Utrecht University Medical Center, Utrecht, the Netherlands
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18Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
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3Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
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19Diabetes & Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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20Department of Health, National Institute for Health and Welfare, Helsinki, Finland
21Dasman Diabetes Institute, Dasman, Kuwait
22Department of Clinical Neurosciences and Preventive Medicine, Danube University Krems, Krems, Austria
23Saudi Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia
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24Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
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25Department of Genetics, University of North Carolina, Chapel Hill, NC
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2Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
18Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
26Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
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27Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
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18Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
27Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
28Oxford Biomedical Research Centre, National Institute for Health Research, Churchill Hospital, Oxford, U.K.
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29School of Medicine, University of Dundee, Dundee, U.K.
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30Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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31Institute of Neuroscience, National Research Council, Padova, Italy
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4Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
5Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA
32Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA
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33Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
34Department of Pediatrics, University of California, Los Angeles, Los Angeles, CA
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35Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA
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2Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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2Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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36Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
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2Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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33Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA
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37Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
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38Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO
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39Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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40Wake Forest School of Medicine, Winston-Salem, NC
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8Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ
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7Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC
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2Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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41Institute of Cellular Medicine, Newcastle University, Newcastle, U.K.
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4Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
5Diabetes & Obesity Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA
32Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA
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6Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
42Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
43Department of Epidemiology and Biostatistics, EMGO+ Institute for Health and Care Research, VU University Medical Center, Amsterdam, the Netherlands
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8Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ
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1Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, U.K.
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A.R.W., A.J., A.U.J., N.W., and N.v.L. contributed equally to this work.
Diabetes 2017;66(8):2296–2309
Citation
Andrew R. Wood, Anna Jonsson, Anne U. Jackson, Nan Wang, Nienke van Leewen, Nicholette D. Palmer, Sayuko Kobes, Joris Deelen, Lorena Boquete-Vilarino, Jussi Paananen, Alena Stančáková, Dorret I. Boomsma, Eco J.C. de Geus, Elisabeth M.W. Eekhoff, Andreas Fritsche, Mark Kramer, Giel Nijpels, Annemarie Simonis-Bik, Timon W. van Haeften, Anubha Mahajan, Michael Boehnke, Richard N. Bergman, Jaakko Tuomilehto, Francis S. Collins, Karen L. Mohlke, Karina Banasik, Christopher J. Groves, Mark I. McCarthy, Diabetes Research on Patient Stratification (DIRECT), Ewan R. Pearson, Andrea Natali, Andrea Mari, Thomas A. Buchanan, Kent D. Taylor, Anny H. Xiang, Anette P. Gjesing, Niels Grarup, Hans Eiberg, Oluf Pedersen, Yii-Derr Chen, Markku Laakso, Jill M. Norris, Ulf Smith, Lynne E. Wagenknecht, Leslie Baier, Donald W. Bowden, Torben Hansen, Mark Walker, Richard M. Watanabe, Leen M. ‘t Hart, Robert L. Hanson, Timothy M. Frayling; A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants. _Diabetes 1 August 2017; 66 (8): 2296–2309. https://doi.org/10.2337/db16-1452
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Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose–raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose–raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide–based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.
© 2017 by the American Diabetes Association.
2017
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