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Diabetes. 2014 Jun;63(6):2158-71. doi: 10.2337/db13-0949. Epub 2013 Dec 2.

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.

Author information

1
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Alexander Fleming, Biomedical Sciences Research Center, Vari, Athens, Greece.
2
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
3
Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
4
Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
5
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.Estonian Genome Center, University of Tartu, Tartu, Estonia.
6
Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, CanadaGeneral Medicine Division, Massachusetts General Hospital, Boston, MA.
7
Department of Biology and Evolution, University of Ferrara, Ferrara, Italy.
8
Boston University Data Coordinating Center, Boston, MA.
9
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
10
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
11
Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, Germany.
12
Steno Diabetes Center, Gentofte, Denmark.
13
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
14
Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY.
15
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA.
16
CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, France.
17
Wellcome Trust Sanger Institute, Hinxton, U.K.University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
18
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
19
IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, Germany.
20
Wellcome Trust Sanger Institute, Hinxton, U.K.
21
Department of Medicine III, Division of Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.
22
Interdisciplinary Center for Clinical Research Leipzig, Leipzig, Germany.
23
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
24
IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, GermanyDepartment of Medicine, University of Leipzig, Leipzig, Germany.
25
CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, FranceDepartment of Genomics of Common Disease, Imperial College London, London, U.K.
26
CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, FranceDepartment of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.
27
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
28
Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
29
Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
30
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
31
Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, FinlandCentre for Vascular Prevention, Danube University Krems, Krems, AustriaKing Abdulaziz University, Jeddah, Saudi Arabia.
32
Department of Medical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden.
33
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkFaculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
34
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkHagedorn Research Institute, Copenhagen, DenmarkInstitute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DenmarkFaculty of Health Sciences, University of Aarhus, Aarhus, Denmark.
35
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
36
Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, GermanyDepartment of Clinical Nutrition, German Institute of Human Nutrition, Nuthetal, Germany.
37
General Medicine Division, Massachusetts General Hospital, Boston, MADepartment of Medicine, Harvard Medical School, Boston, MA.
38
Department of Biostatistics, Boston University School of Public Health, Boston, MAThe National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.
39
Departments of Preventive Medicine and Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
40
Department of Medicine, Harvard Medical School, Boston, MACenter for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MAProgram in Medical and Population Genetics, Broad Institute, Cambridge, MA.
41
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
42
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
43
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.Department of Genomics of Common Disease, Imperial College London, London, U.K.

Abstract

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

PMID:
24296717
PMCID:
PMC4030103
DOI:
10.2337/db13-0949
[Indexed for MEDLINE]
Free PMC Article

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