Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity.

Autor:	Deshmukh HA; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Madsen AL; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Viñuela A; Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva., Have CT; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Grarup N; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Tura A; Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, Padua, Italy., Mahajan A; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK., Heggie AJ; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Koivula RW; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 205 02 Malmö, Sweden., De Masi F; Integrative Systems Biology Group, Department of Health Technology, Technical University of Denmark (DTU), Kemitorvet, Building 208, 2800 Kgs. Lyngby, Denmark., Tsirigos KK; Integrative Systems Biology Group, Department of Health Technology, Technical University of Denmark (DTU), Kemitorvet, Building 208, 2800 Kgs. Lyngby, Denmark., Linneberg A; Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Drivsholm T; Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark.; Section of General Practice, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen, Øster Farimagsgade 5, Copenhagen, Denmark., Pedersen O; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Sørensen TIA; Novo Nordisk Foundation Centre for Basic Metabolic Research (Section of Metabolic Genetics), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Public Health (Section of Epidemiology), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Astrup A; Department of Nutrition, Exercise and Sports (NEXS), Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Gjesing AAP; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Pavo I; Eli Lilly Regional Operations Ges.m.b.H., Koelblgasse 8-10, Vienna, Austria., Wood AR; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK., Ruetten H; Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt, 65926 Frankfurt am Main, Germany., Jones AG; NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK., Koopman ADM; Department of Epidemiology and Biostatistics, VUMC, de Boelelaan 1089a, HV, Amsterdam, the Netherlands., Cederberg H; Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland., Rutters F; Department of Epidemiology and Biostatistics, VUMC, de Boelelaan 1089a, HV, Amsterdam, the Netherlands., Ridderstrale M; Department of Clinical Sciences, Diabetes & Endocrinology Unit, Lund University, Skåne University Hospital Malmö, CRC, 91-12, 205 02, Malmö, Sweden., Laakso M; Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland., McCarthy MI; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK., Frayling TM; Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK., Ferrannini E; CNR Institute of Clinical Physiology, Pisa, Italy., Franks PW; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 205 02 Malmö, Sweden.; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts.; Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden., Pearson ER; Division of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK., Mari A; Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, Padua, Italy., Hansen T; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Walker M; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2021 Jan 01; Vol. 106 (1), pp. 80-90.
DOI:	10.1210/clinem/dgaa653
Abstrakt:	Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. Objective: To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. Design: We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. Results: Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10-9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10-9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. Conclusion: We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity. (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu