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

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  • Harshal A Deshmukh
  • Ana Viñuela
  • Christian Theil Have
  • Niels Grarup
  • Andrea Tura
  • Anubha Mahajan
  • Alison J Heggie
  • Robert W Koivula
  • Federico De Masi
  • 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

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 non-diabetic subjects from 6 independent cohorts (n=5,706). Beta-cell glucose sensitivity was calculated from mixed-meal and oral glucose tolerance tests, and its associations between known glycaemia related SNPS and GWAS SNPs were estimated using linear regression models.

Results: Beta-cell glucose sensitivity was moderately heritable (h2 ranged between 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=2.64x10-9) and rs9368219 in the CDKAL1 (P-value=3.15x10-9) 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.

TidsskriftJournal of Clinical Endocrinology and Metabolism
Udgave nummer1
Sider (fra-til)80-90
Antal sider11
StatusUdgivet - 2021

Bibliografisk note

CURIS 2021 NEXS 070

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