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Robert Koivula

Robert Koivula

Assistant researcher

Robert Koivula

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

Author

  • Harshal A. Deshmukh
  • Anne Lundager Madsen
  • Ana Viñuela
  • Christian Theil Have
  • Niels Grarup
  • Andrea Tura
  • Anubha Mahajan
  • Alison J. Heggie
  • Robert W. Koivula
  • Federico De Masi
  • Konstantinos K. Tsirigos
  • Allan Linneberg
  • Thomas Drivsholm
  • Oluf Pedersen
  • Thorkild I.A. Sørensen
  • Arne Astrup
  • Anette A.P. Gjesing
  • Imre Pavo
  • Andrew R. Wood
  • Hartmut Ruetten
  • Angus G. Jones
  • Anitra D.M. Koopman
  • Henna Cederberg
  • Femke Rutters
  • Martin Ridderstrale
  • Markku Laakso
  • Mark I. McCarthy
  • Tim M. Frayling
  • Ele Ferrannini
  • Paul W. Franks
  • Ewan R. Pearson
  • Andrea Mari
  • Torben Hansen
  • Mark Walker

Summary, in English

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.

Department/s

  • Genetic and Molecular Epidemiology
  • Genomics, Diabetes and Endocrinology
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2021

Language

English

Pages

80-90

Publication/Series

The Journal of clinical endocrinology and metabolism

Volume

106

Issue

1

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Endocrinology and Diabetes
  • Medical Genetics

Keywords

  • beta-cell function
  • diabetes progression
  • Glucose intolerance
  • incretin
  • mathematical model

Status

Published

Research group

  • Genetic and Molecular Epidemiology
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 1945-7197