Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Year: 2014

Type: article

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.

Source: Carolina Digital Repository (University of North Carolina at Chapel Hill)

DOI: 10.17615/5vbx-b108

Authors: Antigone S. Dimas, Vasiliki Lagou, Adam Barker, Joshua W. Knowles, Reedik Maegi, Marie‐France Hivert, Andrea Benazzo, Denis Rybin, Anne Jackson, Heather M. Stringham, Ci Song, Antje Fischer-Rosinský, Trine Welløv Boesgaard, Niels Grarup, Fahim Abbasi, Themistocles L. Assimes, Ke Hao, Xia Yang, Cécile Lecœur, Inês Barroso, Lori L. Bonnycastle, Yvonne Boettcher, Suzannah Bumpstead, Peter S. Chines, Michael R. Erdos, J. Graessler, Péter Kovács, Mario A. Morken, Narisu Narisu, Felicity Payne, Alena Stančáková, Amy J. Swift, Anke Toenjes, Stefan R. Bornstein, Stéphane Cauchi, Philippe Froguel, David Meyre, Peter E. H. Schwarz, Hans-Ulrich Haering, 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, A. Pfeiffer, Joachim Spranger, Michael Stümvoll, James B. Meigs, Nicholas J. Wareham, Johanna Kuusisto, Markku Laakso, Claudia Langenberg, Josée Dupuis, Richard M. Watanabe, José C. Florez, Erik Ingelsson, Mark I. McCarthy, Inga Prokopenko

Language: English

Topic: Genetic Associations and Epidemiology

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: American Heart Association, AstraZeneca, GlaxoSmithKline, Massachusetts General Hospital, Takeda Pharmaceuticals North America, School of Medicine, Boston University, Wellcome Trust, Broad Institute, Incyte, National Institute for Health and Care Research, University of Oxford, European Commission, European Foundation for the Study of Diabetes, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Stiftelsen för Strategisk Forskning, Academy of Finland, Bundesministerium für Bildung und Forschung, Daiichi-Sankyo, Lundbeckfonden, Hjärt-Lungfonden, Vetenskapsrådet, Akademiska Sjukhuset, Uppsala Universitet, Boehringer Ingelheim Stiftung, H. Lundbeck A/S, Diabetesforeningen, National Institutes of Health, Centers for Disease Control and Prevention, U.S. Public Health Service, Medical Research Council, NIHR Cambridge Biomedical Research Centre, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources

OpenAlex ID: W2796954261