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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A Genome-Wide Association Study of IVGTT-Based Measures of First Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants. / Wood, Andrew R; Jonsson, Anna; Jackson, Anne U; Wang, Tian-Nan; van Leewen, Nienke; Palmer, Nicholette D; Kobes, Sayuko; Deelen, Joris; Boquete-Vilarino, Lorena; Paananen, Jussi; Stančáková, Alena; Boomsma, Dorret I; de Geus, Eco Jc; Eekhoff, Elisabeth Mw; Fritsche, Andreas; Kramer, Mark; Nijpels, Giel; Simonis-Bik, Annemarie M C; van Haeften, Timon W; Mahajan, Anubha; Boehnke, Michael; Bergman, Richard N; Tuomilehto, Jaakko; Collins, Francis S; Mohlke, Karen L; Banasik, Karina; Groves, Christopher J; McCarthy, Mark I; Pearson, Ewan R; Natali, Andrea; Mari, Andrea; Buchanan, Thomas A; Taylor, Kent D; Xiang, Anny H; Gjesing, Anette P; Grarup, Niels; Eiberg, Hans; Pedersen, Oluf; Chen, Yii-Derr; Laakso, Markku; Norris, Jill M; Smith, Ulf; Wagenknecht, Lynne E; Baier, Leslie; Bowden, Donald W; Hansen, Torben; Walker, Mark; Watanabe, Richard M; 't Hart, Leen M; Hanson, Robert L; Frayling, Timothy M.
In: Diabetes, Vol. 66, No. 8, 2017, p. 2296-2309.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
Y1 - 2017
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 genome-wide 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 genome-wide 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.
U2 - 10.2337/db16-1452
DO - 10.2337/db16-1452
M3 - Journal article
C2 - 28490609
VL - 66
SP - 2296
EP - 2309
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 8
ER -
ID: 179620437