A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

Andrew R Wood; Anna Jonsson; Anne U Jackson; Tian-Nan Wang; Nienke van Leewen; Nicholette D Palmer; Sayuko Kobes; Joris Deelen; Lorena Boquete-Vilarino; Jussi Paananen; Alena Stančáková; Dorret I Boomsma; Eco Jc de Geus; Elisabeth Mw Eekhoff; Andreas Fritsche; Mark Kramer; Giel Nijpels; Annemarie M C Simonis-Bik; Timon W van Haeften; Anubha Mahajan; Michael Boehnke; Richard N Bergman; Jaakko Tuomilehto; Francis S Collins; Karen L Mohlke; Karina Banasik; Christopher J Groves; Mark I McCarthy; Ewan R Pearson; Andrea Natali; Andrea Mari; Thomas A Buchanan; Kent D Taylor; Anny H Xiang; Anette P Gjesing; Niels Grarup; Hans Eiberg; Oluf Pedersen; Yii-Derr Chen; Markku Laakso; Jill M Norris; Ulf Smith; Lynne E Wagenknecht; Leslie Baier; Donald W Bowden; Torben Hansen; Mark Walker; Richard M Watanabe; Leen M 't Hart; Robert L Hanson; Timothy M Frayling

doi:10.2337/db16-1452

A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

Andrew R Wood, Anna Jonsson, Anne U Jackson, Tian-Nan Wang, Nienke van Leewen, Nicholette D Palmer, Sayuko Kobes, Joris Deelen, Lorena Boquete-Vilarino, Jussi Paananen, Alena Stančáková, Dorret I Boomsma, Eco Jc de Geus, Elisabeth Mw Eekhoff, Andreas Fritsche, Mark Kramer, Giel Nijpels, Annemarie M C Simonis-Bik, Timon W van Haeften, Anubha MahajanMichael Boehnke, Richard N Bergman, Jaakko Tuomilehto, Francis S Collins, Karen L Mohlke, Karina Banasik, Christopher J Groves, Mark I McCarthy, Ewan R Pearson, Andrea Natali, Andrea Mari, Thomas A Buchanan, Kent D Taylor, Anny H Xiang, Anette P Gjesing, Niels Grarup, Hans Eiberg, Oluf Pedersen, Yii-Derr Chen, Markku Laakso, Jill M Norris, Ulf Smith, Lynne E Wagenknecht, Leslie Baier, Donald W Bowden, Torben Hansen, Mark Walker, Richard M Watanabe, Leen M 't Hart, Robert L Hanson, Timothy M Frayling

44 Citations (Scopus)

Abstract

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genomewide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.

Original language	English
Journal	Diabetes
Volume	66
Issue number	8
Pages (from-to)	2296-2309
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db16-1452
Publication status	Published - Aug 2017

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Wood, A. R., Jonsson, A., Jackson, A. U., Wang, T.-N., van Leewen, N., Palmer, N. D., Kobes, S., Deelen, J., Boquete-Vilarino, L., Paananen, J., Stančáková, A., Boomsma, D. I., de Geus, E. J., Eekhoff, E. M., Fritsche, A., Kramer, M., Nijpels, G., Simonis-Bik, A. M. C., van Haeften, T. W., ... Frayling, T. M. (2017). A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants. Diabetes, 66(8), 2296-2309. https://doi.org/10.2337/db16-1452

Wood, AR, Jonsson, A, Jackson, AU, Wang, T-N, van Leewen, N, Palmer, ND, Kobes, S, Deelen, J, Boquete-Vilarino, L, Paananen, J, Stančáková, A, Boomsma, DI, de Geus, EJ, Eekhoff, EM, Fritsche, A, Kramer, M, Nijpels, G, Simonis-Bik, AMC, van Haeften, TW, Mahajan, A, Boehnke, M, Bergman, RN, Tuomilehto, J, Collins, FS, Mohlke, KL, Banasik, K, Groves, CJ, McCarthy, MI, Pearson, ER, Natali, A, Mari, A, Buchanan, TA, Taylor, KD, Xiang, AH, Gjesing, AP , Grarup, N , Eiberg, H , Pedersen, O, Chen, Y-D, Laakso, M, Norris, JM, Smith, U, Wagenknecht, LE, Baier, L, Bowden, DW, Hansen, T, Walker, M, Watanabe, RM, 't Hart, LM, Hanson, RL & Frayling, TM 2017, 'A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants', Diabetes, vol. 66, no. 8, pp. 2296-2309. https://doi.org/10.2337/db16-1452

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title = "A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants",

abstract = "Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genomewide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.",

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year = "2017",

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doi = "10.2337/db16-1452",

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journal = "Diabetes",

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T1 - A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

AU - Wood, Andrew R

AU - Jonsson, Anna

AU - Jackson, Anne U

AU - Wang, Tian-Nan

AU - van Leewen, Nienke

AU - Palmer, Nicholette D

AU - Kobes, Sayuko

AU - Deelen, Joris

AU - Boquete-Vilarino, Lorena

AU - Paananen, Jussi

AU - Stančáková, Alena

AU - Boomsma, Dorret I

AU - de Geus, Eco Jc

AU - Eekhoff, Elisabeth Mw

AU - Fritsche, Andreas

AU - Kramer, Mark

AU - Nijpels, Giel

AU - Simonis-Bik, Annemarie M C

AU - van Haeften, Timon W

AU - Mahajan, Anubha

AU - Boehnke, Michael

AU - Bergman, Richard N

AU - Tuomilehto, Jaakko

AU - Collins, Francis S

AU - Mohlke, Karen L

AU - Banasik, Karina

AU - Groves, Christopher J

AU - McCarthy, Mark I

AU - Pearson, Ewan R

AU - Natali, Andrea

AU - Mari, Andrea

AU - Buchanan, Thomas A

AU - Taylor, Kent D

AU - Xiang, Anny H

AU - Gjesing, Anette P

AU - Grarup, Niels

AU - Eiberg, Hans

AU - Pedersen, Oluf

AU - Chen, Yii-Derr

AU - Laakso, Markku

AU - Norris, Jill M

AU - Smith, Ulf

AU - Wagenknecht, Lynne E

AU - Baier, Leslie

AU - Bowden, Donald W

AU - Hansen, Torben

AU - Walker, Mark

AU - Watanabe, Richard M

AU - 't Hart, Leen M

AU - Hanson, Robert L

AU - Frayling, Timothy M

PY - 2017/8

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N2 - Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genomewide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.

AB - Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genomewide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.

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DO - 10.2337/db16-1452

M3 - Journal article

C2 - 28490609

SN - 0012-1797

VL - 66

SP - 2296

EP - 2309

JO - Diabetes

JF - Diabetes

IS - 8

ER -

A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

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