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PMID: 24296717 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Review

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

Diabetes ·Vol. 63 ·No. 6 ·2014-06-00 ·Pages 2158-71

Dimas AS, Lagou V, Barker A, Knowles JW, Mägi R, Hivert MF, Benazzo A, Rybin D, Jackson AU, Stringham HM, Song C, Fischer-Rosinsky A, Boesgaard TW, Grarup N, Abbasi FA, Assimes TL, Hao K, Yang X, Lecoeur C, Barroso I, Bonnycastle LL, Böttcher Y, Bumpstead S, Chines PS, Erdos MR, Graessler J, Kovacs P, Morken MA, Narisu N, Payne F, Stancakova A, Swift AJ, Tönjes A, Bornstein SR, Cauchi S, Froguel P, Meyre D, Schwarz PE, Häring HU, Smith U, Boehnke M, Bergman RN, Collins FS, Mohlke KL, Tuomilehto J, Quertemous T, Lind L, Hansen T, Pedersen O, Walker M, Pfeiffer AF, Spranger J, Stumvoll M, Meigs JB, Wareham NJ, Kuusisto J, Laakso M, Langenberg C, Dupuis J, Watanabe RM, Florez JC, Ingelsson E, McCarthy MI, Prokopenko I, MAGIC Investigators

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.

MeSH Terms
Alleles Cluster Analysis Diabetes Mellitus, Type 2/genetics Female Gene Frequency Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Humans Insulin/metabolism Insulin Resistance/genetics Insulin Secretion Insulin-Secreting Cells/metabolism Male Polymorphism, Single Nucleotide Quantitative Trait Loci/genetics Risk Factors Transcription Factors/metabolism
Chemicals
Insulin Transcription Factors
Authors & Affiliations
65 authors, click to expand affiliations / ORCID
Dimas Antigone S
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Alexander Fleming, Biomedical Sciences Research Center, Vari, Athens, Greece.
Lagou Vasiliki
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
Barker Adam
Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
Knowles Joshua W
Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
Mägi Reedik
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.
Hivert Marie-France
Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, CanadaGeneral Medicine Division, Massachusetts General Hospital, Boston, MA.
Benazzo Andrea
Department of Biology and Evolution, University of Ferrara, Ferrara, Italy.
Rybin Denis
Boston University Data Coordinating Center, Boston, MA.
Jackson Anne U
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
Stringham Heather M
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
Song Ci
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Fischer-Rosinsky Antje
Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, Germany.
Boesgaard Trine Welløv
Steno Diabetes Center, Gentofte, Denmark.
Grarup Niels
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abbasi Fahim A
Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
Assimes Themistocles L
Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
Hao Ke
Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY.
Yang Xia
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA.
Lecoeur Cécile
CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, France.
Barroso Inês
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.
Bonnycastle Lori L
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
Böttcher Yvonne
IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, Germany.
Bumpstead Suzannah
Wellcome Trust Sanger Institute, Hinxton, U.K.
Chines Peter S
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
Erdos Michael R
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
Graessler Jurgen
Department of Medicine III, Division of Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.
Kovacs Peter
Interdisciplinary Center for Clinical Research Leipzig, Leipzig, Germany.
Morken Mario A
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
Narisu Narisu
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
Payne Felicity
Wellcome Trust Sanger Institute, Hinxton, U.K.
Stancakova Alena
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Swift Amy J
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
Tönjes Anke
IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, GermanyDepartment of Medicine, University of Leipzig, Leipzig, Germany.
Bornstein Stefan R
Department of Medicine III, Division of Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.
Cauchi Stéphane
CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, France.
Froguel Philippe
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.
Meyre David
CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, FranceDepartment of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.
Schwarz Peter E H
Department of Medicine III, Division of Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.
Häring Hans-Ulrich
Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
Smith Ulf
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.
Boehnke Michael
Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
Bergman Richard N
Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Collins Francis S
Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
Mohlke Karen L
Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
Tuomilehto Jaakko
Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, FinlandCentre for Vascular Prevention, Danube University Krems, Krems, AustriaKing Abdulaziz University, Jeddah, Saudi Arabia.
Quertemous Thomas
Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
Lind Lars
Department of Medical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden.
Hansen Torben
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.
Pedersen Oluf
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.
Walker Mark
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
Pfeiffer Andreas F H
Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, GermanyDepartment of Clinical Nutrition, German Institute of Human Nutrition, Nuthetal, Germany.
Spranger Joachim
Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, Germany.
Stumvoll Michael
IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, GermanyDepartment of Medicine, University of Leipzig, Leipzig, Germany.
Meigs James B
General Medicine Division, Massachusetts General Hospital, Boston, MADepartment of Medicine, Harvard Medical School, Boston, MA.
Wareham Nicholas J
Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
Kuusisto Johanna
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Laakso Markku
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Langenberg Claudia
Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
Dupuis Josée
Department of Biostatistics, Boston University School of Public Health, Boston, MAThe National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.
Watanabe Richard M
Departments of Preventive Medicine and Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Florez Jose C
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.
Ingelsson Erik
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.
McCarthy Mark I
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.
Prokopenko Inga
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.
MAGIC Investigators
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Article Info
Journal
Diabetes
Abbr.
Diabetes
ISSN
1939-327X
DOI
10.2337/db13-0949
Published
2014-06-00
Epub
2013-00-02
Pages
2158-71
Language
English
Region
United States
NLM ID
0372763
PMCID
PMC4030103
Subset
IM
Grants
NIDDK NIH HHS · K24 DK-080140 · United States
NIDDK NIH HHS · R56 DK062370 · United States
NIDDK NIH HHS · DK-069922 · United States
NIDDK NIH HHS · R01 DK-078616 · United States
NCRR NIH HHS · RR01066 · United States
NHLBI NIH HHS · N02HL64278 · United States
Medical Research Council · MC_U106179471 · United Kingdom
NCRR NIH HHS · 2 M01 RR000070 · United States
Wellcome Trust · 090532 · United Kingdom
NIDDK NIH HHS · U01 DK062370 · United States
NHLBI NIH HHS · N01HC25195 · United States
NIDA NIH HHS · U54 DA021519 · United States
NCRR NIH HHS · M01 RR000070 · United States
NIDDK NIH HHS · R01 DK093757 · United States
NIDDK NIH HHS · R01 DK078616 · United States
NHLBI NIH HHS · N02-HL-6-4278 · United States
NHLBI NIH HHS · N01-HC-25195 · United States
Wellcome Trust · 098381 · United Kingdom
NIDDK NIH HHS · DK-062370 · United States
NIDDK NIH HHS · R01 DK072193 · United States
Medical Research Council · MC_UU_12015/1 · United Kingdom
NIDDK NIH HHS · R01 DK062370 · United States
NCRR NIH HHS · M01 RR001066 · United States
Medical Research Council · G1002084 · United Kingdom
Intramural NIH HHS · Z01 HG000024-13 · United States
Medical Research Council · G0701863 · United Kingdom
Intramural NIH HHS · Z01 HG000024 · United States
NIDDK NIH HHS · K24 DK080140 · United States
NIDDK NIH HHS · P30 DK020572 · United States
Wellcome Trust · United Kingdom
NIDDK NIH HHS · R01 DK069922 · United States
NIDDK NIH HHS · DK-072193 · United States
Corrections
CommentIn
PMID: 24853896
External Links
PubMed source DOI: 10.2337/db13-0949 PMC Full Text View journal details
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