Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity

Harshal A. Deshmukh; Anne Lundager Madsen; Ana Viñuela; Christian Theil Have; Niels Grarup; Andrea Tura; Anubha Mahajan; Alison J. Heggie; Robert W. Koivula; Federico De Masi; Konstantinos K. Tsirigos; Allan Linneberg; Thomas Drivsholm; Oluf Pedersen; Thorkild I.A. Sørensen; Arne Astrup; Anette A.P. Gjesing; Imre Pavo; Andrew R. Wood; Hartmut Ruetten; Angus G. Jones; Anitra D.M. Koopman; Henna Cederberg; Femke Rutters; Martin Ridderstrale; Markku Laakso; Mark I. McCarthy; Tim M. Frayling; Ele Ferrannini; Paul W. Franks; Ewan R. Pearson; Andrea Mari; Torban Hansen; Mark Walker

doi:10.1210/clinem/dgaa653

Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity

Harshal A. Deshmukh, Anne Lundager Madsen, Ana Viñuela, Christian Theil Have, Niels Grarup, Andrea Tura, Anubha Mahajan, Alison J. Heggie, Robert W. Koivula, Federico De Masi, Konstantinos K. Tsirigos, Allan Linneberg, Thomas Drivsholm, Oluf Pedersen, Thorkild I.A. Sørensen, Arne Astrup, Anette A.P. Gjesing, Imre Pavo, Andrew R. Wood, Hartmut RuettenAngus G. Jones, Anitra D.M. Koopman, Henna Cederberg, Femke Rutters, Martin Ridderstrale, Markku Laakso, Mark I. McCarthy, Tim M. Frayling, Ele Ferrannini, Paul W. Franks, Ewan R. Pearson, Andrea Mari, Torban Hansen, Mark Walker

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucoseinsulin 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 genomewide 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

Original language	English
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	106
Issue number	1
Pages (from-to)	80-90
ISSN	0021-972X
DOIs	https://doi.org/10.1210/clinem/dgaa653
Publication status	Published - 2020

Keywords

Glucose intolerance
Diabetes progression
Beta-cell function
Incretin
Mathematical model

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Deshmukh, H. A., Madsen, A. L., Viñuela, 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., Sørensen, T. I. A., Astrup, A., Gjesing, A. A. P., Pavo, I., Wood, A. R., ... Walker, M. (2020). Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity. Journal of Clinical Endocrinology and Metabolism, 106(1), 80-90. https://doi.org/10.1210/clinem/dgaa653

Deshmukh, Harshal A. ; Madsen, Anne Lundager ; Viñuela, Ana ; Have, Christian Theil ; Grarup, Niels ; Tura, Andrea ; Mahajan, Anubha ; Heggie, Alison J. ; Koivula, Robert W. ; De Masi, Federico ; Tsirigos, Konstantinos K. ; Linneberg, Allan ; Drivsholm, Thomas ; Pedersen, Oluf ; Sørensen, Thorkild I.A. ; Astrup, Arne ; Gjesing, Anette A.P. ; Pavo, Imre ; Wood, Andrew R. ; Ruetten, Hartmut ; Jones, Angus G. ; Koopman, Anitra D.M. ; Cederberg, Henna ; Rutters, Femke ; Ridderstrale, Martin ; Laakso, Markku ; McCarthy, Mark I. ; Frayling, Tim M. ; Ferrannini, Ele ; Franks, Paul W. ; Pearson, Ewan R. ; Mari, Andrea ; Hansen, Torban ; Walker, Mark. / Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity. In: Journal of Clinical Endocrinology and Metabolism. 2020 ; Vol. 106, No. 1. pp. 80-90.

@article{6e047176eb874c50b8aa4e23973f2011,

title = "Genome-Wide Association Analysis of Pancreatic Beta Cell Glucose Sensitivity",

abstract = "Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucoseinsulin 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 genomewide 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, Diabetes progression, Beta-cell function, Incretin, Mathematical model",

author = "Deshmukh, {Harshal A.} and Madsen, {Anne Lundager} and Ana Vi{\~n}uela and Have, {Christian Theil} and Niels Grarup and Andrea Tura and Anubha Mahajan and Heggie, {Alison J.} and Koivula, {Robert W.} and {De Masi}, Federico and Tsirigos, {Konstantinos K.} and Allan Linneberg and Thomas Drivsholm and Oluf Pedersen and S{\o}rensen, {Thorkild I.A.} and Arne Astrup and Gjesing, {Anette A.P.} and Imre Pavo and Wood, {Andrew R.} and Hartmut Ruetten and Jones, {Angus G.} and Koopman, {Anitra D.M.} and Henna Cederberg and Femke Rutters and Martin Ridderstrale and Markku Laakso and McCarthy, {Mark I.} and Frayling, {Tim M.} and Ele Ferrannini and Franks, {Paul W.} and Pearson, {Ewan R.} and Andrea Mari and Torban Hansen and Mark Walker",

year = "2020",

doi = "10.1210/clinem/dgaa653",

language = "English",

volume = "106",

pages = "80--90",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

number = "1",

}

Deshmukh, HA, Madsen, AL, Viñuela, A, Have, CT, Grarup, N, Tura, A, Mahajan, A, Heggie, AJ, Koivula, RW, De Masi, F, Tsirigos, KK, Linneberg, A, Drivsholm, T, Pedersen, O, Sørensen, TIA, Astrup, A, Gjesing, AAP, Pavo, I, Wood, AR, Ruetten, H, Jones, AG, Koopman, ADM, Cederberg, H, Rutters, F, Ridderstrale, M, Laakso, M, McCarthy, MI, Frayling, TM, Ferrannini, E, Franks, PW, Pearson, ER, Mari, A, Hansen, T & Walker, M 2020, '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

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.; De Masi, Federico; Tsirigos, Konstantinos K.; Linneberg, Allan; Drivsholm, Thomas; Pedersen, Oluf; Sørensen, Thorkild I.A.; Astrup, Arne; Gjesing, Anette A.P.; Pavo, Imre; Wood, Andrew R.; Ruetten, Hartmut; Jones, Angus G.; Koopman, Anitra D.M.; Cederberg, Henna; Rutters, Femke; Ridderstrale, Martin; Laakso, Markku; McCarthy, Mark I.; Frayling, Tim M.; Ferrannini, Ele; Franks, Paul W.; Pearson, Ewan R.; Mari, Andrea; Hansen, Torban; Walker, Mark.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 106, No. 1, 2020, p. 80-90.

Research output: Contribution to journal › Journal article › Research › peer-review

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

PY - 2020

Y1 - 2020

N2 - Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucoseinsulin 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 genomewide 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 glucoseinsulin 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 genomewide 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 - Diabetes progression

KW - Beta-cell function

KW - Incretin

KW - Mathematical model

U2 - 10.1210/clinem/dgaa653

DO - 10.1210/clinem/dgaa653

M3 - Journal article

C2 - 32944759

VL - 106

SP - 80

EP - 90

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 1

ER -