Genome-wide association analysis of pancreatic beta cell glucose sensitivity
Research output: Contribution to journal › Journal article › Research › peer-review
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 non-diabetic subjects from 6 independent cohorts (n=5,706). Beta-cell glucose sensitivity was calculated from mixed-meal and oral glucose tolerance tests, and its associations between known glycaemia related SNPS and GWAS SNPs were estimated using linear regression models.
Results: Beta-cell glucose sensitivity was moderately heritable (h2 ranged between 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=2.64x10-9) and rs9368219 in the CDKAL1 (P-value=3.15x10-9) 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.
|Journal||The Journal of clinical endocrinology and metabolism|
|Publication status||Accepted/In press - 18 Sep 2020|
© Endocrine Society 2020.
- Faculty of Science - Glucose intolerance, Diabetes progression, Beta cell function, Incretin, Mathematical model