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

Lookup NU author(s): Dr Harshal Deshmukh, Dr Ana Viñuela, Dr Alison Heggie, Professor Mark Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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


Publication metadata

Author(s): Deshmukh HA, Madsen AL, Vinuela A, Have CT, Grarup N, Tura A, Mahajan A, Heggie AJ, Koivula RW, De Masi F, Tsirigos KK, Linneberg A, Drivsholm T, Pedersen O, Sorensen TIA, Astrup A, Gjesing AAP, Pavo I, Wood AR, Ruetten H, Jones AG, Koopman ADM, Cederberg H, Rutters F, Ridderstrale M, Laakso M, McCarthy MI, Frayling TM, Ferrannini E, Franks PW, Pearson ER, Mari A, Hansen T, Walker M

Publication type: Article

Publication status: Published

Journal: The Journal of Clinical Endocrinology & Metabolism

Year: 2021

Volume: 106

Issue: 1

Pages: 80-90

Print publication date: 01/01/2021

Online publication date: 18/09/2020

Acceptance date: 14/09/2020

Date deposited: 19/03/2021

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Oxford University Press

URL: https://doi.org/10.1210/clinem/dgaa653

DOI: 10.1210/clinem/dgaa653

PubMed id: 32944759


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