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

Harshal Deshmukh ,Allan Linneberg ,Thomas Drivsholm ,Mark Mccarthy ,Tim Frayling ,Anitra D.m Koopman ,Paul W Franks ,Martin Ridderstråle ,Torben Hansen ,Andrea Mari ,Anubha Mahajan ,Hartmut Ruetten ,Andrew R Wood ,Oluf Pedersen ,Andrea Tura ,Anne Lundager Madsen ,Robert W Koivula ,Ewan R Pearson ,Anette A P Gjesing ,Konstantinos D Tsirigos ,Federico De Masi ,Henna Cederberg ,Markku Laakso ,Ana Viñuela ,Alison Heggie ,Imre Pávó ,Angus G Jones ,Niels Grarup ,Ele Ferrannini ,Arne Astrup ,Thorkild I A Sørensen ,Christian Theil Have ,Femke Rutters ,Mark Walker

doi:10.1210/clinem/dgaa653

Abstract

ContextPancreatic 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.ObjectiveTo understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies.DesignWe 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.ResultsBeta-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.ConclusionWe show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.

Highlights

D mixed meal tolerance tests (OGTT and MMTT, respectively) using C-peptide kinetic analysis to measure insulin secretion rates [2]
For the known single nucleotide polymorphism (SNP) associated with type 2 diabetes and glycemic traits (P < 0.01), we examined the overlap between their association with beta-cell glucose sensitivity in our study and the early peak insulin response to an intravenous glucose challenge (IVGTT) as previously reported [19]
The key finding is that variation at the CDKAL1 and GIPR-QPCTL regions showed the strongest associations with beta-cell glucose sensitivity in the entire study cohort, and when the analysis was limited to nondiabetic subjects

Summary

Introduction

D mixed meal tolerance tests (OGTT and MMTT, respectively) using C-peptide kinetic analysis to measure insulin secretion rates [2]. It assesses beta-cell glucose sensitivity under conditions that reflect daily living in contrast to intravenous glucose–based methods that exclude the incretin system. It is independent of potential confounders, such as hepatic insulin clearance, that can influence circulating insulin levels and impact on measures of beta-cell function that examine changes in insulin levels in response to a glucose challenge. The aims of this study were to define the heritability of beta-cell glucose sensitivity and to perform genome-wide association and candidate gene (known diabetes and glycemic risk loci) association analyses for beta-cell glucose sensitivity across a range of glucose tolerance

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Conclusion