TY - JOUR
T1 - Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity
AU - Deshmukh, Harshal A.
AU - Madsen, Anne Lundager
AU - Viñuela, Ana
AU - Have, Christian Theil
AU - Grarup, Niels
AU - Tura, Andrea
AU - Mahajan, Anubha
AU - Heggie, Alison J.
AU - Koivula, Robert W.
AU - De Masi, Federico
AU - Tsirigos, Konstantinos K.
AU - Linneberg, Allan
AU - Drivsholm, Thomas
AU - Pedersen, Oluf
AU - Sørensen, Thorkild I. A.
AU - Astrup, Arne
AU - Gjesing, Anette A. P.
AU - Pavo, Imre
AU - Wood, Andrew R.
AU - Ruetten, Hartmut
AU - Jones, Angus G.
AU - Koopman, Anitra D. M.
AU - Cederberg, Henna
AU - Rutters, Femke
AU - Ridderstrale, Martin
AU - Laakso, Markku
AU - McCarthy, Mark I.
AU - Frayling, Tim M.
AU - Ferrannini, Ele
AU - Franks, Paul W.
AU - Pearson, Ewan R.
AU - Mari, Andrea
AU - Hansen, Torban
AU - Walker, Mark
N1 - Funding Information:
The work leading to this publication was funded by the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contribution. We acknowledge the support of the DIRECT Consortium (6) European Union's Horizon 2020 research and innovation program (grant agreement No 667191), the Novo Nordisk Foundation Center for Basic Metabolic Research which is an independent Research Center based at the University of Copenhagen, Denmark and partially funded by an unconditional donation from the Novo Nordisk Foundation (www.cbmr.ku.dk) (Grant number NNF18CC0034900.), and the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406 The ADIGEN study was supported by grants from The Danish Medical Research Council, The Danish National Research Foundation, and The Velux Foundation. We thank Professor George Davey Smith, Bristol University, for his contribution to the male- GOYA GWAS. The Family study was supported by grants from the Danish Medical Research Council; the University of Copenhagen; an EEC grant (BMH4CT950662); the Velux Foundation; the Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction and Care (LUCAMP; www.lucamp.org); the European Foundation for the Study of Diabetes (EFSD) and the Danish Diabetes Association. [Genetics DIRECT] The 1936-cohort acknowledges support of the Danish Heart Foundation, and the Danish Medical Research Council financially supported the 1996/97 investigation ERP holds a Wellcome Trust New Investigator Award (102820/Z/13/Z). The work undertaken by P.W.F was supported in part by ERC-2015-CoG-NASCENT-681742.
Publisher Copyright:
© 2020 The Author(s).
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Glucose intolerance
KW - beta-cell function
KW - diabetes progression
KW - incretin
KW - mathematical model
UR - http://www.scopus.com/inward/record.url?scp=85099072735&partnerID=8YFLogxK
U2 - 10.1210/clinem/dgaa653
DO - 10.1210/clinem/dgaa653
M3 - Article
C2 - 32944759
SN - 0021-972X
VL - 106
SP - 80
EP - 90
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 1
ER -
