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

Author:

Deshmukh Harshal A1ORCID,Madsen Anne Lundager2,Viñuela Ana3,Have Christian Theil2,Grarup Niels2ORCID,Tura Andrea4ORCID,Mahajan Anubha56,Heggie Alison J1,Koivula Robert W67,De Masi Federico8,Tsirigos Konstantinos K8,Linneberg Allan910,Drivsholm Thomas911,Pedersen Oluf2,Sørensen Thorkild I A1213,Astrup Arne14,Gjesing Anette A P2,Pavo Imre15,Wood Andrew R16,Ruetten Hartmut17,Jones Angus G18,Koopman Anitra D M19,Cederberg Henna20,Rutters Femke19,Ridderstrale Martin21,Laakso Markku22,McCarthy Mark I23,Frayling Tim M16,Ferrannini Ele24,Franks Paul W672526,Pearson Ewan R27,Mari Andrea4,Hansen Torben2,Walker Mark1ORCID

Affiliation:

1. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

2. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

3. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva

4. Institute of Neuroscience, National Research Council, Corso Stati Uniti 4, Padua, Italy

5. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK

6. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

7. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Lund University, 205 02 Malmö, Sweden

8. Integrative Systems Biology Group, Department of Health Technology, Technical University of Denmark (DTU), Kemitorvet, Building 208, 2800 Kgs. Lyngby, Denmark

9. Center for Clinical Research and Disease Prevention, Bispebjerg and Frederiksberg Hospital, The Capital Region, Copenhagen, Denmark

10. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

11. Section of General Practice, Institute of Public Health, Faculty of Health Sciences, University of Copenhagen, Øster Farimagsgade 5, Copenhagen, Denmark

12. Novo Nordisk Foundation Centre for Basic Metabolic Research (Section of Metabolic Genetics), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

13. Department of Public Health (Section of Epidemiology), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

14. Department of Nutrition, Exercise and Sports (NEXS), Faculty of Science, University of Copenhagen, Copenhagen, Denmark

15. Eli Lilly Regional Operations Ges.m.b.H., Koelblgasse 8–10, Vienna, Austria

16. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK

17. Diabetes Division, Sanofi-Aventis Deutschland GmbH, Frankfurt, 65926 Frankfurt am Main, Germany

18. NIHR Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, UK

19. Department of Epidemiology and Biostatistics, VUMC, de Boelelaan 1089a, HV, Amsterdam, the Netherlands

20. Department of Endocrinology, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland

21. Department of Clinical Sciences, Diabetes & Endocrinology Unit, Lund University, Skåne University Hospital Malmö, CRC, 91-12, 205 02, Malmö, Sweden

22. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland

23. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK

24. CNR Institute of Clinical Physiology, Pisa, Italy

25. Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts

26. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

27. Division of Population Health & Genomics, School of Medicine, University of Dundee, Dundee, UK

Abstract

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.

Funder

Novo Nordisk Fonden

Danish National Research Foundation

Velux Fonden

Danish Medical Research Council

University of Copenhagen

European Foundation for the Study of Diabetes

Danish Diabetes Association

Publisher

The Endocrine Society

Subject

Biochemistry (medical),Clinical Biochemistry,Endocrinology,Biochemistry,Endocrinology, Diabetes and Metabolism

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