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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity
Diabetes, Volume 63, No. 6, Year 2014
Notification
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Description
Patients with established type 2 diabetes display both b-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. © 2014 by the American Diabetes Association.
Authors & Co-Authors
Dimas, Antigone S.
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Greece, Vari
Biomedical Sciences Research Center Alexander Fleming
Lagou, Vasiliki
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Barker, Adam
United Kingdom, Cambridge
Addenbrooke's Hospital
Knowles, Joshua W.
United States, Stanford
Stanford University School of Medicine
Mägi, Reedik
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Oxford
University of Oxford Medical Sciences Division
Estonia, Tartu
Tartu Ülikooli Genoomika Instituut
Hivert, Marie France
Canada, Sherbrooke
Université de Sherbrooke
United States, Boston
Massachusetts General Hospital
Benazzo, Andrea
Italy, Ferrara
University of Ferrara
Rybin, Denis V.
United States, Boston
Boston University
Jackson, Anne U.
United States, Ann Arbor
University of Michigan School of Public Health
Stringham, Heather M.
United States, Ann Arbor
University of Michigan School of Public Health
Song, Ci
Sweden, Uppsala
Uppsala Universitet
Sweden, Stockholm
Karolinska Institutet
Fischer-Rosinský, Antje
Germany, Berlin
Charité – Universitätsmedizin Berlin
Welløv Boesgaard, Trine
Denmark, Herlev
Steno Diabetes Center Copenhagen
Grarup, Niels
Denmark, Copenhagen
Novo Nordisk Foundation Center for Basic Metabolic Research
Abbasi, Fahim A.
United States, Stanford
Stanford University School of Medicine
Assimes, Themistocles L.
United States, Stanford
Stanford University School of Medicine
Hao, Ke
United States, New York
Icahn School of Medicine at Mount Sinai
Yang, Xia
United States, Los Angeles
University of California, Los Angeles
Lecoeur, Cécile
France, Lille
Institut Pasteur de Lille
Barroso, Inês E.
United Kingdom, Hinxton
Wellcome Sanger Institute
United Kingdom, Cambridge
University of Cambridge
Bonnycastle, Lori L.C.
United States, Bethesda
National Human Genome Research Institute Nhgri
Böttcher, Yvonne
Germany, Leipzig
Universitätsklinikum Leipzig Und Medizinische Fakultät
Bumpstead, Suzannah J.
United Kingdom, Hinxton
Wellcome Sanger Institute
Chines, Peter S.
Greece, Vari
Biomedical Sciences Research Center Alexander Fleming
Erdos, Michael R.
United States, Bethesda
National Human Genome Research Institute Nhgri
Graessler, Juergen
Germany, Dresden
Technische Universität Dresden
Kovács, Péter F.
Germany, Leipzig
Universitätsklinikum Leipzig Und Medizinische Fakultät
Morken, Mario A.
United States, Bethesda
National Human Genome Research Institute Nhgri
Narisu, Narisu
United States, Bethesda
National Human Genome Research Institute Nhgri
Payne, Felicity
United Kingdom, Hinxton
Wellcome Sanger Institute
Stančáková, Alena
Finland, Kuopio
Itä-suomen Yliopisto
Swift, Amy J.
United States, Bethesda
National Human Genome Research Institute Nhgri
Tönjes, Anke
Germany, Leipzig
Universitätsklinikum Leipzig Und Medizinische Fakultät
Germany, Leipzig
Universität Leipzig
Bornstein, Stefan R.
Germany, Dresden
Technische Universität Dresden
Cauchi, Stéphane S.
France, Lille
Institut Pasteur de Lille
Froguel, Philippe
France, Lille
Institut Pasteur de Lille
United Kingdom, London
Imperial College London
Meyre, David
France, Lille
Institut Pasteur de Lille
Canada, Hamilton
Mcmaster University
Schwarz, Peter Ee H.
Germany, Dresden
Technische Universität Dresden
Häring, Hans Ulrich
Germany, Tubingen
Eberhard Karls Universität Tübingen
Smith, Ulf P.G.
Sweden, Gothenburg
Sahlgrenska Akademin
Boehnke, Michael L.
United States, Ann Arbor
University of Michigan School of Public Health
Bergman, Richard N.
United States, Los Angeles
Keck School of Medicine of Usc
Collins, Francis S.
United States, Bethesda
National Human Genome Research Institute Nhgri
Mohlke, Karen
United States, Chapel Hill
The University of North Carolina at Chapel Hill
Tuomilehto, Jaakko O.I.
Finland, Helsinki
Terveyden ja Hyvinvoinnin Laitos
Austria, Krems an Der Donau
Donau-universität Krems
Saudi Arabia, Jeddah
King Abdulaziz University
Assimes, Themistocles L.
United States, Stanford
Stanford University School of Medicine
Lind, Lars L.
Sweden, Uppsala
Akademiska Sjukhuset
Hansen, Torben Frøstrup
Denmark, Copenhagen
Novo Nordisk Foundation Center for Basic Metabolic Research
Denmark, Odense
Faculty of Health Sciences, University of Southern Denmark
Pedersen, Oluf Borbye
Denmark, Copenhagen
Novo Nordisk Foundation Center for Basic Metabolic Research
Denmark, Gentofte
Hagedorn Research Institute
Denmark, Copenhagen
Det Sundhedsvidenskabelige Fakultet
Denmark, Aarhus
Fakultetet Health
Walker, Mark A.
United Kingdom, Newcastle
University of Newcastle Upon Tyne, Faculty of Medical Sciences
Pfeiffer, Andreas F.H.
Germany, Berlin
Charité – Universitätsmedizin Berlin
Germany, Nuthetal
German Institute of Human Nutrition
Spranger, Joachim Andreas
Germany, Berlin
Charité – Universitätsmedizin Berlin
Stumvoll, Michael W.
Germany, Leipzig
Universitätsklinikum Leipzig Und Medizinische Fakultät
Germany, Leipzig
Universität Leipzig
Meigs, James B.
United States, Boston
Massachusetts General Hospital
United States, Boston
Harvard Medical School
Wareham, Nicholas J.
United Kingdom, Cambridge
Addenbrooke's Hospital
Kuusisto, Johanna K.
Finland, Kuopio
Itä-suomen Yliopisto
Laakso, M. M.
Finland, Kuopio
Itä-suomen Yliopisto
Langenberg, Claudia C.
United Kingdom, Cambridge
Addenbrooke's Hospital
Dupuis, Josèe
United States, Boston
Boston University
United States, Framingham
Framingham Heart Study
Watanabe, Richard M.
United States, Los Angeles
Keck School of Medicine of Usc
Florez, Jose C.
United States, Boston
Harvard Medical School
United States, Boston
Massachusetts General Hospital
United States, Cambridge
Broad Institute
Ingelsson, Erik
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
Sweden, Uppsala
Uppsala Universitet
McCarthy, Mark I.
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Oxford
University of Oxford Medical Sciences Division
United Kingdom, Oxford
Churchill Hospital
Prokopenko, Inga I.
United Kingdom, Oxford
The Wellcome Centre for Human Genetics
United Kingdom, Oxford
University of Oxford Medical Sciences Division
United Kingdom, London
Imperial College London
Statistics
Citations: 300
Authors: 64
Affiliations: 46
Identifiers
Doi:
10.2337/db13-0949
ISSN:
00121797
e-ISSN:
1939327X
Research Areas
Genetics And Genomics
Noncommunicable Diseases
Study Approach
Quantitative