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

Deshmukh, Harshal A. ; Madsen, Anne Lundager ; Viñuela, Ana ; Have, Christian Theil ; Grarup, Niels ; Tura, Andrea ; Mahajan, Anubha ; Heggie, Alison J. ; Koivula, Robert W. LU and De Masi, Federico , et al. (2021) In The Journal of clinical endocrinology and metabolism 106(1). p.80-90
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
beta-cell function, diabetes progression, Glucose intolerance, incretin, mathematical model
in
The Journal of clinical endocrinology and metabolism
volume
106
issue
1
pages
11 pages
publisher
Oxford University Press
external identifiers
  • pmid:32944759
  • scopus:85099072735
ISSN
1945-7197
DOI
10.1210/clinem/dgaa653
language
English
LU publication?
yes
id
b2374eac-85fc-43a3-ae93-ef61967a98ed
date added to LUP
2021-01-20 11:21:29
date last changed
2021-06-16 04:31:41
@article{b2374eac-85fc-43a3-ae93-ef61967a98ed,
  abstract     = {<p>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.</p>},
  author       = {Deshmukh, Harshal A. and Madsen, Anne Lundager and Viñuela, Ana and Have, Christian Theil and Grarup, Niels and Tura, Andrea and Mahajan, Anubha and Heggie, Alison J. and Koivula, Robert W. and De Masi, Federico and Tsirigos, Konstantinos K. and Linneberg, Allan and Drivsholm, Thomas and Pedersen, Oluf and Sørensen, Thorkild I.A. and Astrup, Arne and Gjesing, Anette A.P. and Pavo, Imre and Wood, Andrew R. and Ruetten, Hartmut and Jones, Angus G. and Koopman, Anitra D.M. and Cederberg, Henna and Rutters, Femke and Ridderstrale, Martin and Laakso, Markku and McCarthy, Mark I. and Frayling, Tim M. and Ferrannini, Ele and Franks, Paul W. and Pearson, Ewan R. and Mari, Andrea and Hansen, Torben and Walker, Mark},
  issn         = {1945-7197},
  language     = {eng},
  number       = {1},
  pages        = {80--90},
  publisher    = {Oxford University Press},
  series       = {The Journal of clinical endocrinology and metabolism},
  title        = {Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity},
  url          = {http://dx.doi.org/10.1210/clinem/dgaa653},
  doi          = {10.1210/clinem/dgaa653},
  volume       = {106},
  year         = {2021},
}