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Meta-Analysis
. 2021 Jan 1;106(1):80-90.
doi: 10.1210/clinem/dgaa653.

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

Harshal A Deshmukh  1 , Anne Lundager Madsen  2 , Ana Viñuela  3 , Christian Theil Have  2 , Niels Grarup  2 , Andrea Tura  4 , Anubha Mahajan  5   6 , Alison J Heggie  1 , Robert W Koivula  6   7 , Federico De Masi  8 , Konstantinos K Tsirigos  8 , Allan Linneberg  9   10 , Thomas Drivsholm  9   11 , Oluf Pedersen  2 , Thorkild I A Sørensen  12   13 , Arne Astrup  14 , Anette A P Gjesing  2 , Imre Pavo  15 , Andrew R Wood  16 , Hartmut Ruetten  17 , Angus G Jones  18 , Anitra D M Koopman  19 , Henna Cederberg  20 , Femke Rutters  19 , Martin Ridderstrale  21 , Markku Laakso  22 , Mark I McCarthy  23 , Tim M Frayling  16 , Ele Ferrannini  24 , Paul W Franks  6   7   25   26 , Ewan R Pearson  27 , Andrea Mari  4 , Torben Hansen  2 , Mark Walker  1
Affiliations
Meta-Analysis

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

Harshal A Deshmukh et al. J Clin Endocrinol Metab. .

Erratum in

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 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.

Keywords: Glucose intolerance; beta-cell function; diabetes progression; incretin; mathematical model.

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Figures

Figure 1.
Figure 1.
Manhattan plot of genome-wide P values of association for beta-cell glucose sensitivity: horizontal upper and lower lines represent the suggestive genome-wide significance thresholds of p <10−7 and p <10–5, respectively.
Figure 2.
Figure 2.
Q-Q plot of genome-wide P values of association for beta-cell glucose sensitivity of the observed versus expected P values given the number of statistical tests performed for beta-cell glucose sensitivity.
Figure 3.
Figure 3.
Regional association plot of GIPR-QPCTL gene region. Plot produced in Locus Zoom with the most strongly associated SNP (rs2238691) shown as the purple diamond.
Figure 4.
Figure 4.
Regional association plot of CDKAL1 gene region. Plot produced in LocusZoom with the most strongly associated SNP (rs9368219) shown as the purple diamond.
See this image and copyright information in PMC

References

    1. Byrne MM, Sturis J, Sobel RJ, Polonsky KS. Elevated plasma glucose 2 h postchallenge predicts defects in beta-cell function. Am J Physiol. 1996;270(4 Pt 1):E572-E579. - PubMed
    1. Mari A, Schmitz O, Gastaldelli A, Oestergaard T, Nyholm B, Ferrannini E. Meal and oral glucose tests for assessment of beta -cell function: modeling analysis in normal subjects. Am J Physiol Endocrinol Metab. 2002;283(6):E1159-E1166. - PubMed
    1. Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab. 2005;90(1):493-500. - PubMed
    1. Walker M, Mari A, Jayapaul MK, Bennett SM, Ferrannini E. Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects. Diabetologia. 2005;48(12):2470-2476. - PubMed
    1. Tura A, Grassi A, Winhofer Y, et al. . Progression to type 2 diabetes in women with former gestational diabetes: time trajectories of metabolic parameters. PLoS One. 2012;7(11):e50419. - PMC - PubMed

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