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Bispebjerg Hospital - a part of Copenhagen University Hospital
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Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity

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  • 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
  • Torban Hansen
  • Mark Walker
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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.

Original languageEnglish
JournalThe Journal of clinical endocrinology and metabolism
Volume106
Issue number1
Pages (from-to)80-90
Number of pages11
ISSN0021-972X
DOIs
Publication statusPublished - 1 Jan 2021

Bibliographical note

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

ID: 60882895