Your browser has javascript turned off or blocked. This will lead to some parts of our website to not work properly or at all. Turn on javascript for best performance.

The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Paul Franks

Paul Franks

Principal investigator

Paul Franks

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 in 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