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New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 4 , 4 , 5 , 4 , 5 , 5 ,   5 , 14 , 15 , 16 , 17 , 18 , 19 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 5 , 27 , 28 , 29 , 30 , 31 , 31 , 32 , 6 , 7 , 10 , 33 , 34 , 35 , 13 , 36 , 37 , 38 , 21 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 3 , 6 , 7 , 6 , 7 , 11 , 11 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 4 , 14 , 15 , 15 , 57 , 13 , 47 , 58 , 59 , 60 , 36 , 8 , 61 , 62 , 47 , 63 ,   17 , 64 , 37 , 6 , 65 , 38 , 23 , 13 , 13 , 47 , 64 , 66 , 67 , 68 , 3 , 2 , 69 , 70 , 71 , 72 , 62 , 73 , 4 , 74 , 8 , 75 , 76 , 77 , 8 , 10 , 78 , 4 , 25 , 79 , 80 , 81 , 82 , 66 , 83 , 36 , 22 , 52 , 84 , 85 , 86 , 87 , 88 , 4 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ,   36 , 98 , 99 , 100 , 101 , 79 , 38 , 13 , 13 , 10 , 102 , 103 , 9 , 1 , 39 , 6 , 104 , 105 , 4 , 106 , 21 , 28 , 13 , 45 , 47 , 66 , 83 , 65 , 47 , 4 , 107 , 108 , 65 , 45 , 109 , 110 , 82 , 47 , 5 , 27 , 42 , 96 , 111 , 112 , 67 , 68 , 82 , 113 , 23 , 114 , 8 , 115 , 44 , 116 , 117 , 118 , 4 , 5 , 119 , 96 , 111 , 22 , 120 , 81 , 121 , 122 , 123 , 3 , 124 , 65 , 125 , 126 , 10 , 127 , 3 , 98 , 55 , 56 , 22 , 120 , 128 , 64 , 66 , 129 , 130 , 131 , 17 , 47 , 125 , 132 , 133 , 134 , 21 , 135 , 60 , 136 , 87 , 137 , 22 , 120 , 70 , 138 , 120 , 8 , 139 , 25 , 140 , 141 , 96 , 111 , 142 , 19 , 64 , 66 , 5 , 27 , 28 , 24 , 23 , 22 , 143 , 5 , 8 , 79 , 43 , 144 , 9 , 3 , 120 , DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, 44 , 3 , 80 , 42 , 104 , 105 , 69 , 105 , 98 , 96 , 111 , 146 , 38 , 73 , 73 , 67 , 68 , 4 , 107 , 45 , 125 , 34 , 39 , 109 , 132 , 64 , 66 , 84 , 147 , 148 , 149 , 150 , 36 , 33 , 151 , 152 , 153 , 154 , 155 , 155 , 31 , 156 , 31 , 59 , 157 , 82 , 158 , 159 , 21 , 160 , 161 , 21 , 24 , 162 , 163 , 25 , 60 , 24 , 24 , 128 , 164 , 164 , 165 , 47 , 166 , 94 , 167 , 167 , 6 , 7 , 104 , 105 , 62 , 168 , 140 , 23 , 8 , 8 , 9 , 28 , 169 , 19 , 19 , 170 , 19 , 170 , 22 , 22 , 65 , 65 , 171 , 47 , 65 , 172 , 17 , 93 , 173 , 26 , 141 , 8 , 48 , 96 , 111 , 112 , 26 , 10 , 3 , 40 , 41 , 13 , 142 , 164 , 174 , 35 , 105 , 102 , 10 , 4 , 5 , 107 , 6 , 7 , 104 , 105 , 11 , for the MAGIC investigators

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      Abstract

      Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.

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      Quantifying heterogeneity in a meta-analysis.

      The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity. Copyright 2002 John Wiley & Sons, Ltd.
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        Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.

        The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
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          Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.

           R Turner,  C Fox,  DR Matthews (1998)
          Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)
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            Author and article information

            Affiliations
            [1 ]Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA
            [2 ]National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts 01702, USA
            [3 ]MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
            [4 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK
            [5 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
            [6 ]Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA
            [7 ]Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
            [8 ]Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
            [9 ]Twin Research & Genetic Epidemiology Department, King’s College London, St Thomas' Hospital Campus, Lambeth Palace Rd, London SE1 7EH, UK
            [10 ]Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, USA
            [11 ]Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
            [12 ]Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington, USA
            [13 ]CNRS-UMR8090, Pasteur Institute, Lille 2-Droit et Santé University, F-59000 Lille, France
            [14 ]Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland
            [15 ]University Institute of Social and Preventative Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, 1005 Lausanne, Switzerland
            [16 ]Swiss Institute of Bioinformatics, Switzerland
            [17 ]Department of Epidemiology and Public Health, Imperial College of London, Faculty of Medicine, Norfolk Place, London W2 1PG, UK
            [18 ]Boston University Data Coordinating Center, Boston, Massachusetts 02118, USA
            [19 ]deCODE Genetics, 101 Reykjavik, Iceland
            [20 ]Department of Human Genetics, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
            [21 ]Institute of Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany
            [22 ]Department of Epidemiology, Erasmus MC Rotterdam, 3000 CA, The Netherlands
            [23 ]Department of Biological Psychology, VU, Van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands
            [24 ]Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK
            [25 ]MRC Human Genetics Unit, IGMM, Edinburgh EH4 2XU, UK
            [26 ]Division of Genetics, R&D, Glaxo SmithKline, King of Prussia, Pennsylvania 19406, USA
            [27 ]Department of Cardiovascular Medicine, University of Oxford, Oxford OX3 9DU, UK
            [28 ]Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter EX1 2LU, UK
            [29 ]Laboratory of Clinical Investigation, National Institute of Aging, Baltimore, Maryland 21250, USA
            [30 ]Unit for Child and Adolescent Health and Welfare, National Institute for Health and Welfare, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland
            [31 ]Hagedorn Research Institute, 2820 Gentofte, Denmark
            [32 ]Department of Medicine & Therapeutics, Level 7, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK
            [33 ]Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21287, USA
            [34 ]Department of Nutrition - Dietetics, Harokopio University, 17671 Athens, Greece
            [35 ]General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts, USA
            [36 ]Department of Epidemiology and Public Health, University College London, UK
            [37 ]Depts. of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
            [38 ]MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol BS8 2PR, UK
            [39 ]Fundación para la Investigación Biomédica del Hospital Clínico San Carlos, Madrid, Spain
            [40 ]Departments of Medicine and Human Genetics, McGill University, Montreal, Canada
            [41 ]Genome Quebec Innovation Centre, Montreal H3A 1A4, Canada
            [42 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
            [43 ]Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden
            [44 ]Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA
            [45 ]Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
            [46 ]INSERM U859, Universite de Lille-Nord de France, F-59000 Lille, France
            [47 ]Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA
            [48 ]The Broad Institute, Cambridge, Massachusetts 02141, USA
            [49 ]Leiden Genome Technology Center, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
            [50 ]INSERM U780-IFR69, Paris Sud University, F-94807 Villejuif, France
            [51 ]The Heart Research Institute, Sydney, New South Wales, Australia
            [52 ]PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, NEDLANDS WA 6009, Australia
            [53 ]School of Surgery and Pathology, University of Western Australia, Nedlands WA 6009, Australia
            [54 ]Department of Social Medicine, University of Bristol, Bristol BS8 2PR, UK
            [55 ]Landspitali University Hospital, 101 Reykjavik, Iceland
            [56 ]Icelandic Heart Association, 201 Kopavogur, Iceland
            [57 ]The Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas 77030, USA
            [58 ]Steno Diabetes Center, DK-2820 Gentofte, Copenhagen, Denmark
            [59 ]Faculty of Health Science, University of Aarhus, Aarhus DK-8000, Denmark
            [60 ]Department of Medicine, University of Leipzig, Liebigstr. 18, 04103 Leipzig, Germany
            [61 ]Endocrinology-Diabetology Unit, Corbeil-Essonnes Hospital, Essonnes, F-91108 France
            [62 ]Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
            [63 ]Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford OX3 7LF, UK
            [64 ]Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Perth, Australia
            [65 ]Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy
            [66 ]Western Australian Sleep Disorders Research Institute, Queen Elizabeth Medical Centre II, Perth, Australia
            [67 ]Department of Endocrinology, Diabetes and Nutrition, Charite-Universitaetsmedizin Berlin, Berlin, Germany
            [68 ]Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
            [69 ]Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
            [70 ]Department of Human Genetics, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
            [71 ]Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy
            [72 ]U557 Institut National de la Santé et de la Recherche Médicale, U1125 Institut National de la Recherche Agronomique, Université Paris 13, 74 rue Marcel Cachin, 93017 Bobigny Cedex, France
            [73 ]Department of Medicine III, Division Prevention and Care of Diabetes, University of Dresden, 01307 Dresden
            [74 ]Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA
            [75 ]Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden
            [76 ]CHU de Poitiers, Endocrinologie Diabetologie, CIC INSERM 0802, INSERM U927, Université de Poitiers, UFR, Médecine Pharmacie, Poitiers, France
            [77 ]Department of Public Health & Clinical Medicine, Section for Nutritional Research, Umeå University, Umeå, Sweden
            [78 ]Department of Clinical Sciences, Obstetrics and Gynecology, University of Oulu, Box 5000, Fin-90014 University of Oulu, Finland
            [79 ]Centre National de Génotypage/IG/CEA, 2 rue Gaston Crémieux CP 5721, 91057 Evry Cedex, France
            [80 ]U872 Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Paris Descartes, 15 rue de l’Ecole de Médecine, 75270 Paris Cedex, France
            [81 ]Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
            [82 ]Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Viale Druso 1, 39100 Bolzano, Italy, Affiliated Institute of the University Lübeck, Germany
            [83 ]Department of Pulmonary Physiology, Sir Charles Gairdner Hospital, Perth, Australia
            [84 ]Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia
            [85 ]Heart Institute of Western Australia, Sir Charles Gairdner Hospital, Nedlands WA 6009, Australia
            [86 ]School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA 6009, Australia
            [87 ]Folkhalsan Research Centre, Helsinki, Finland
            [88 ]Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
            [89 ]Nuffield Department of Surgery, University of Oxford, Oxford OX3 9DU, UK
            [90 ]Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
            [91 ]Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark
            [92 ]National Institute for Health and Welfare, Unit of Population Studies, Turku, Finland
            [93 ]Institute of Health Sciences and Biocenter Oulu, Box 5000, Fin-90014 University of Oulu, Finland
            [94 ]Department of Public Health, Faculty of Medicine, P.O. Box 41 (Mannerheimintie 172), University of Helsinki, 00014 Helsinki, Finland
            [95 ]National Institute for Health and Welfare, Unit for Child and Adolescent Mental Health, Helsinki, Finland
            [96 ]Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
            [97 ]Department of Internal Medicine and Biocenter Oulu, Oulu, Finland
            [98 ]Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX2 5DW, UK
            [99 ]National Institute for Health and Welfare, Unit of Living Conditions, Health and Wellbeing, Helsinki, Finland
            [100 ]Interdisciplinary Centre for Clinical Research, University of Leipzig, Inselstr. 22, 04103 Leipzig, Germany
            [101 ]The Danish Twin Registry, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9B, 5000 Odense, Denmark
            [102 ]Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden
            [103 ]Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA
            [104 ]Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, Massachusetts 02114, USA
            [105 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
            [106 ]Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
            [107 ]Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK
            [108 ]Department of Clinical Genetics, Erasmus MC Rotterdam, 3000 CA, The Netherlands
            [109 ]Biomedical Research Institute, University of Dundee, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK
            [110 ]Department of Geriatric Medicine and Metabolic Disease, Second University of Naples, Naples, Italy.
            [111 ]National Institute for Health and Welfare, Unit of Public Health Genomics, Helsinki, Finland
            [112 ]Department of Medical Genetics, University of Helsinki, Helsinki, Finland
            [113 ]Department of Medical Statistics, Epidemiology and Medical Informatics, Andrija Stampar School of Public Health, Medical School, University of Zagreb, Rockefellerova 4, 10000 Zagreb, Croatia
            [114 ]Department of Clinical Genetics, VUMC, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands
            [115 ]Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulu, Finland
            [116 ]Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington, USA
            [117 ]Group Health Center for Health Studies, Seattle, Washington, USA
            [118 ]Institute of Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
            [119 ]Department of Biostatistics, University of Washington, Seattle, Washington 98195, USA
            [120 ]Department of Internal Medicine, Erasmus MC Rotterdam, 3000 CA, The Netherlands
            [121 ]Department of Medicine/Metabolic Diseases, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
            [122 ]Department of Public Health & Clinical Medicine, Section for Family Medicine, Umeå University Hospital, Umeå, Sweden
            [123 ]School of Public Health, Department of General Practice, University of Aarhus, Aarhus DK-8000, Denmark
            [124 ]Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK
            [125 ]MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
            [126 ]Department of Epidemiology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, 77030, USA
            [127 ]Leibniz-Institut für Arterioskleroseforschung an der Universität Münster,Münster, Germany
            [128 ]Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
            [129 ]Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA
            [130 ]Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA
            [131 ]Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, Washington, USA
            [132 ]Department of Medical Sciences, Uppsala University, Uppsala, Sweden
            [133 ]Medstar Research Institute, Baltimore, Maryland 21250, USA
            [134 ]Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 21250, USA
            [135 ]Institut interrégional pour la santé (IRSA), F-37521 La Riche, France
            [136 ]Coordination Centre for Clinical Trials, University of Leipzig, Härtelstr. 16-18, 04103 Leipzig, Germany
            [137 ]Department of Medicine, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
            [138 ]Department of Internal Medicine, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands
            [139 ]Research Unit, Cardiovascular Genetics, Nancy University Henri Poincaré, Nancy, France
            [140 ]EMGO Institute/Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands
            [141 ]Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
            [142 ]Genomic Medicine, Imperial College London, Hammersmith Hospital, W12 0NN, London, UK
            [143 ]Epidemiology & Public Health, Queen's University Belfast, Belfast BT12 6BJ, UK
            [144 ]Medical Products Agency, Uppsala, Sweden
            [146 ]National Institute for Health and Welfare, Unit of Chronic Disease Epidemiology and Prevention, Helsinki, Finland
            [147 ]Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
            [148 ]Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
            [149 ]Genetic Epidemiology & Clinical Research Group, Department of Public Health & Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden
            [150 ]London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
            [151 ]Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA
            [152 ]The Welch Center for Prevention, Epidemiology, and Clinical Research, School of Medicine and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21287, USA
            [153 ]Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55454, USA
            [154 ]Department of Endocrinology and Diabetes, Norfolk and Norwich University Hospital NHS Trust, Norwich, NR1 7UY, UK
            [155 ]Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio 70210, Finland
            [156 ]Faculty of Health Science, University of Southern Denmark, Odense, Denmark
            [157 ]Institute of Biomedical Science, Faculty of Health Science, University of Copenhagen, Denmark
            [158 ]Department of Neurology, General Central Hospital, 39100 Bolzano, Italy
            [159 ]Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
            [160 ]Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
            [161 ]Klinikum Grosshadern, Munich, Germany
            [162 ]School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia
            [163 ]Gen-Info Ltd, Ruzmarinka 17, 10000 Zagreb, Croatia
            [164 ]Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
            [165 ]Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA
            [166 ]Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA
            [167 ]National Institute for Health and Welfare, Unit of Diabetes Prevention, Helsinki, Finland
            [168 ]Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington, USA
            [169 ]Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
            [170 ]Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland
            [171 ]Lab of Cardiovascular Sciences, National Institute on Aging, NIH, Baltimore, Maryland, USA
            [172 ]Department of Clinical Sciences/Clinical Chemistry, University of Oulu, Box 5000, Fin-90014 University of Oulu, Finland
            [173 ]National Institute of Health and Welfare, Aapistie 1, P.O. Box 310, Fin-90101 Oulu, Finland
            [174 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, 90033, USA
            Author notes
            Corresponding authors: Michael Boehnke, Department of Biostatistics and Center for Statistical Genetics, University of Michigan, 1420 Washington Heights, Ann Arbor, MI 48109 – USA, Tel. +1 734 936 1001, Fax. +1 734 615 8322, boehnke@ 123456umich.edu , Mark I. McCarthy, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ – UK, Tel. +44 (0) 1865 857298, Fax. +44 (0) 1865 857299, mark.mccarthy@ 123456drl.ox.ac.uk , Jose C. Florez, Diabetes Research Center (Diabetes Unit), and Center for Human Genetic Research, Simches Research Building – CPZN 5.250, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114 – USA, Tel. +1 617 643 3308, Fax. +1 617 643 6630, jcflorez@ 123456partners.org , Inês Barroso, Metabolic Disease Group, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK, Tel. +44 (0) 1223 495341, Fax. +44 (0) 1223 494919, ib1@ 123456sanger.ac.uk
            [*]

            These authors contributed equally

            [145]

            See appendix for full list of authors

            Contributors
            On behalf of : on behalf of Procardis consortium
            Journal
            9216904
            2419
            Nat Genet
            Nature genetics
            1061-4036
            1546-1718
            25 December 2010
            17 January 2010
            February 2010
            11 January 2011
            : 42
            : 2
            : 105-116
            3018764
            20081858
            10.1038/ng.520
            nihpa259059

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            Funding
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: R01 DK078616-01A1 ||DK
            Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
            Award ID: P30 DK040561-14 ||DK
            Categories
            Article

            Genetics

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