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

Antigone S Dimas; Vasiliki Lagou; Adam Barker; Joshua W Knowles; Reedik Mägi; Marie-France Hivert; Andrea Benazzo; Denis Rybin; Anne U Jackson; Heather M Stringham; Ci Song; Antje Fischer-Rosinsky; Trine Welløv Boesgaard; Niels Grarup; Fahim A Abbasi; Themistocles L Assimes; Ke Hao; Xia Yang; Cécile Lecoeur; Inês Barroso; Lori L Bonnycastle; Yvonne Böttcher; Suzannah Bumpstead; Peter S Chines; Michael R Erdos; Jurgen Graessler; Peter Kovacs; Mario A Morken; Narisu Narisu; Felicity Payne; Alena Stancakova; Amy J Swift; Anke Tönjes; Stefan R Bornstein; Stéphane Cauchi; Philippe Froguel; David Meyre; Peter E H Schwarz; Hans-Ulrich Häring; Ulf Smith; Michael Boehnke; Richard N Bergman; Francis S Collins; Karen L Mohlke; Jaakko Tuomilehto; Thomas Quertemous; Lars Lind; Torben Hansen; Oluf Pedersen; Mark Walker; Andreas F H Pfeiffer; Joachim Spranger; Michael Stumvoll; James B Meigs; Nicholas J Wareham; Johanna Kuusisto; Markku Laakso; Claudia Langenberg; Josée Dupuis; Richard M Watanabe; Jose C Florez; Erik Ingelsson; Mark I McCarthy; Inga Prokopenko; MAGIC Investigators

doi:10.2337/db13-0949

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

Journal article

Open access

Peer reviewed

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

Antigone S Dimas, Vasiliki Lagou, Adam Barker, Joshua W Knowles, Reedik Mägi, Marie-France Hivert, Andrea Benazzo, Denis Rybin, Anne U Jackson, Heather M Stringham, …

Diabetes (New York, N.Y.), Vol.63(6), pp.2158-2171

01/06/2014

DOI: https://doi.org/10.2337/db13-0949

PMID: 24296717

Abstract

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

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.

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Title: Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity
Creators: Antigone S Dimas - Alexander Fleming Biomedical Sciences Research Center
Vasiliki Lagou - Wellcome Centre for Human Genetics
Adam Barker - MRC Epidemiology Unit
Joshua W Knowles - Stanford University
Reedik Mägi - University of Tartu
Marie-France Hivert - Université de Sherbrooke
Andrea Benazzo - University of Ferrara
Denis Rybin - Boston University
Anne U Jackson - University of Michigan–Ann Arbor
Heather M Stringham - University of Michigan–Ann Arbor
Ci Song - Science for Life Laboratory
Antje Fischer-Rosinsky - Charité - Universitätsmedizin Berlin
Trine Welløv Boesgaard - Steno Diabetes Center
Niels Grarup - University of Copenhagen
Fahim A Abbasi - Cardiovascular Institute of the South
Themistocles L Assimes - Cardiovascular Institute of the South
Ke Hao - Icahn School of Medicine at Mount Sinai
Xia Yang - University of California, Los Angeles
Cécile Lecoeur - Université de Lille
Inês Barroso - Wellcome Sanger Institute
Lori L Bonnycastle - National Human Genome Research Institute
Yvonne Böttcher - IFB Adiposity Diseases
Suzannah Bumpstead - Wellcome Sanger Institute
Peter S Chines - National Human Genome Research Institute
Michael R Erdos - National Human Genome Research Institute
Jurgen Graessler - TU Dresden
Peter Kovacs - Interdisciplinary Center for Clinical Research Leipzig, Leipzig, Germany
Mario A Morken - National Human Genome Research Institute
Narisu Narisu - National Human Genome Research Institute
Felicity Payne - Wellcome Sanger Institute
Alena Stancakova - University of Eastern Finland
Amy J Swift - National Human Genome Research Institute
Anke Tönjes - IFB Adiposity Diseases
Stefan R Bornstein - TU Dresden
Stéphane Cauchi - Centre National de la Recherche Scientifique
Philippe Froguel - Imperial College London
David Meyre - McMaster University
Peter E H Schwarz - TU Dresden
Hans-Ulrich Häring - University of Tübingen
Ulf Smith - University of Gothenburg
Michael Boehnke - University of Michigan–Ann Arbor
Richard N Bergman - University of Southern California
Francis S Collins - National Human Genome Research Institute
Karen L Mohlke - University of North Carolina at Chapel Hill
Jaakko Tuomilehto - King Abdulaziz University
Thomas Quertemous - Cardiovascular Institute of the South
Lars Lind - Uppsala University Hospital
Torben Hansen - University of Copenhagen
Oluf Pedersen - University of Copenhagen
Mark Walker - Newcastle University
Andreas F H Pfeiffer - Charité - Universitätsmedizin Berlin
Joachim Spranger - Charité - Universitätsmedizin Berlin
Michael Stumvoll - IFB Adiposity Diseases
James B Meigs - Massachusetts General Hospital
Nicholas J Wareham - MRC Epidemiology Unit
Johanna Kuusisto - Kuopio University Hospital
Markku Laakso - University of Eastern Finland
Claudia Langenberg - MRC Epidemiology Unit
Josée Dupuis - Boston University
Richard M Watanabe - University of Southern California
Jose C Florez - Harvard University
Erik Ingelsson - Science for Life Laboratory
Mark I McCarthy - Wellcome Centre for Human Genetics
Inga Prokopenko - Wellcome Centre for Human Genetics
MAGIC Investigators
Publication Details: Diabetes (New York, N.Y.), Vol.63(6), pp.2158-2171
Date published: 01/06/2014
Grant note: R01 DK062370 / NIDDK NIH HHS Wellcome Trust G0701863 / Medical Research Council R01 DK072193 / NIDDK NIH HHS R01 DK069922 / NIDDK NIH HHS N02-HL-6-4278 / NHLBI NIH HHS 090532 / Wellcome Trust N02HL64278 / NHLBI NIH HHS N01-HC-25195 / NHLBI NIH HHS MC_U106179471 / Medical Research Council
Identifiers: 99928716502346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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