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

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dc.contributor.author Deshmukh, Harshal A.
dc.contributor.author Madsen, Anne Lundager
dc.contributor.author Vinuela, Ana
dc.contributor.author Have, Christian Theil
dc.contributor.author Grarup, Niels
dc.contributor.author Tura, Andrea
dc.contributor.author Mahajan, Anubha
dc.contributor.author Heggie, Alison J.
dc.contributor.author Koivula, Robert W.
dc.contributor.author De Masi, Federico
dc.contributor.author Tsirigos, Konstantinos K.
dc.contributor.author Linneberg, Allan
dc.contributor.author Drivsholm, Thomas
dc.contributor.author Pedersen, Oluf
dc.contributor.author Sorensen, Thorkild I. A.
dc.contributor.author Astrup, Arne
dc.contributor.author Gjesing, Anette A. P.
dc.contributor.author Pavo, Imre
dc.contributor.author Wood, Andrew R.
dc.contributor.author Ruetten, Hartmut
dc.contributor.author Jones, Angus G.
dc.contributor.author Koopman, Anitra D. M.
dc.contributor.author Cederberg, Henna
dc.contributor.author Rutters, Femke
dc.contributor.author Ridderstrale, Martin
dc.contributor.author Laakso, Markku
dc.contributor.author McCarthy, Mark
dc.contributor.author Frayling, Tim M.
dc.contributor.author Ferrannini, Ele
dc.contributor.author Franks, Paul W.
dc.contributor.author Pearson, Ewan R.
dc.contributor.author Mari, Andrea
dc.contributor.author Hansen, Torben
dc.contributor.author Walker, Mark
dc.date.accessioned 2021-03-12T11:36:01Z
dc.date.available 2021-03-12T11:36:01Z
dc.date.issued 2021-01
dc.identifier.citation Deshmukh , H A , Madsen , A L , Vinuela , A , Have , C T , Grarup , N , Tura , A , Mahajan , A , Heggie , A J , Koivula , R W , De Masi , F , Tsirigos , K K , Linneberg , A , Drivsholm , T , Pedersen , O , Sorensen , T I A , Astrup , A , Gjesing , A A P , Pavo , I , Wood , A R , Ruetten , H , Jones , A G , Koopman , A D M , Cederberg , H , Rutters , F , Ridderstrale , M , Laakso , M , McCarthy , M , Frayling , T M , Ferrannini , E , Franks , P W , Pearson , E R , Mari , A , Hansen , T & Walker , M 2021 , ' Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity ' , Journal of Clinical Endocrinology and Metabolism , vol. 106 , no. 1 , pp. 80-90 . https://doi.org/10.1210/clinem/dgaa653
dc.identifier.other PURE: 161157173
dc.identifier.other PURE UUID: b3957aac-2e6f-4920-bcd1-7aea5563f5dd
dc.identifier.other WOS: 000608480200060
dc.identifier.uri http://hdl.handle.net/10138/327932
dc.description.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 x 10(-9)) and rs9368219 in the CDKAL1 (P value = 3.15 x 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. en
dc.format.extent 11
dc.language.iso eng
dc.relation.ispartof Journal of Clinical Endocrinology and Metabolism
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject Glucose intolerance
dc.subject diabetes progression
dc.subject beta-cell function
dc.subject incretin
dc.subject mathematical model
dc.subject GENETIC ARCHITECTURE
dc.subject INSULIN SENSITIVITY
dc.subject RS7754840 G/C
dc.subject CDKAL1
dc.subject RISK
dc.subject TOLERANCE
dc.subject METAANALYSIS
dc.subject VARIANTS
dc.subject POLYMORPHISMS
dc.subject OBESITY
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.title Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity en
dc.type Article
dc.contributor.organization HUS Abdominal Center
dc.contributor.organization Department of Medicine
dc.contributor.organization Clinicum
dc.contributor.organization Endokrinologian yksikkö
dc.contributor.organization Helsinki University Hospital Area
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1210/clinem/dgaa653
dc.relation.issn 0021-972X
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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