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

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva. Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, Padua, Italy. 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. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 205 02 Malmö, Sweden. Integrative Systems Biology Group, Department of Health Technology, Technical University of Denmark (DTU), Kemitorvet, Building 208, 2800 Kgs. Lyngby, Denmark. 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. Section of General Practice, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen, Øster Farimagsgade 5, Copenhagen, Denmark. 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. Department of Nutrition, Exercise and Sports (NEXS), Faculty of Science, University of Copenhagen, Copenhagen, Denmark. Eli Lilly Regional Operations Ges.m.b.H., Koelblgasse 8-10, Vienna, Austria. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK. Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt, 65926 Frankfurt am Main, Germany. NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK. Department of Epidemiology and Biostatistics, VUMC, de Boelelaan 1089a, HV, Amsterdam, the Netherlands. Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland. Department of Clinical Sciences, Diabetes & Endocrinology Unit, Lund University, Skåne University Hospital Malmö, CRC, 91-12, 205 02, Malmö, Sweden. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK. CNR Institute of Clinical Physiology, Pisa, Italy. Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden. Division of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK.

The Journal of clinical endocrinology and metabolism. 2021;(1):80-90
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Abstract

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.

Methodological quality

Publication Type : Meta-Analysis

Metadata

MeSH terms : Glucose