Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity

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 RuettenAngus 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

Research output: Contribution to journalArticlepeer-review

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 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 (h 2 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.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Early online date18 Sep 2020
DOIs
Publication statusE-pub ahead of print - 18 Sep 2020

Keywords

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

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