Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Richa Saxena; Marie-France Hivert; Claudia Langenberg; Toshiko Tanaka; James S Pankow; Peter Vollenweider; Valeriya Lyssenko; Nabila Bouatia-Naji; Josée Dupuis; Anne U Jackson; W H Linda Kao; Man Li; Nicole L Glazer; Alisa K Manning; Jian'an Luan; Heather M Stringham; Inga Prokopenko; Toby Johnson; Niels Grarup; Trine W Boesgaard; Cécile Lecoeur; Peter Shrader; Jeffrey O'Connell; Erik Ingelsson; David J Couper; Kenneth Rice; Kijoung Song; Camilla H Andreasen; Christian Dina; Anna Köttgen; Olivier Le Bacquer; François Pattou; Jalal Taneera; Valgerdur Steinthorsdottir; Denis Rybin; Kristin Ardlie; Michael Sampson; Lu Qi; Mandy van Hoek; Michael N Weedon; Yurii S Aulchenko; Benjamin F Voight; Harald Grallert; Beverley Balkau; Richard N Bergman; Knut Borch-Johnsen; Torben Jørgensen; Thomas Sparsø; Torben Hansen; Oluf Pedersen; GIANT Consortium

doi:10.1038/ng.521

Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Richa Saxena, Marie-France Hivert, Claudia Langenberg, Toshiko Tanaka, James S Pankow, Peter Vollenweider, Valeriya Lyssenko, Nabila Bouatia-Naji, Josée Dupuis, Anne U Jackson, W H Linda Kao, Man Li, Nicole L Glazer, Alisa K Manning, Jian'an Luan, Heather M Stringham, Inga Prokopenko, Toby Johnson, Niels Grarup, Trine W BoesgaardCécile Lecoeur, Peter Shrader, Jeffrey O'Connell, Erik Ingelsson, David J Couper, Kenneth Rice, Kijoung Song, Camilla H Andreasen, Christian Dina, Anna Köttgen, Olivier Le Bacquer, François Pattou, Jalal Taneera, Valgerdur Steinthorsdottir, Denis Rybin, Kristin Ardlie, Michael Sampson, Lu Qi, Mandy van Hoek, Michael N Weedon, Yurii S Aulchenko, Benjamin F Voight, Harald Grallert, Beverley Balkau, Richard N Bergman, Knut Borch-Johnsen, Torben Jørgensen, Thomas Sparsø, Torben Hansen, Oluf Pedersen, GIANT Consortium

468 Citations (Scopus)

Abstract

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, Β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10 15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10 17; ratio of insulin to glucose area under the curve, P = 1.3 × 10 16) and diminished incretin effect (n = 804; P = 4.3 × 10 4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10 16), VPS13C (rs17271305, P = 4.1 × 10 8), GCKR (rs1260326, P = 7.1 × 10 11) and TCF7L2 (rs7903146, P = 4.2 × 10 10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 × 10 18).

Original language	English
Journal	Nature Genetics
Volume	42
Issue number	2
Pages (from-to)	142-8
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.521
Publication status	Published - 1 Feb 2010

Keywords

Adenylate Cyclase
Body Mass Index
Denmark
Diabetes Mellitus, Type 2
Female
Gene Expression Profiling
Gene Expression Regulation
Genetic Loci
Genetic Variation
Genome-Wide Association Study
Glucose
Glucose Tolerance Test
Humans
Incretins
Insulin
Male
Meta-Analysis as Topic
Polymorphism, Single Nucleotide
Proteins
RNA, Messenger
Receptors, Gastrointestinal Hormone

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.521

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Saxena, R., Hivert, M-F., Langenberg, C., Tanaka, T., Pankow, J. S., Vollenweider, P., Lyssenko, V., Bouatia-Naji, N., Dupuis, J., Jackson, A. U., Kao, W. H. L., Li, M., Glazer, N. L., Manning, A. K., Luan, J., Stringham, H. M., Prokopenko, I., Johnson, T., Grarup, N., ... GIANT Consortium (2010). Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nature Genetics, 42(2), 142-8. https://doi.org/10.1038/ng.521

Saxena, R, Hivert, M-F, Langenberg, C, Tanaka, T, Pankow, JS, Vollenweider, P, Lyssenko, V, Bouatia-Naji, N, Dupuis, J, Jackson, AU, Kao, WHL, Li, M, Glazer, NL, Manning, AK, Luan, J, Stringham, HM, Prokopenko, I, Johnson, T, Grarup, N, Boesgaard, TW, Lecoeur, C, Shrader, P, O'Connell, J, Ingelsson, E, Couper, DJ, Rice, K, Song, K, Andreasen, CH, Dina, C, Köttgen, A, Le Bacquer, O, Pattou, F, Taneera, J, Steinthorsdottir, V, Rybin, D, Ardlie, K, Sampson, M, Qi, L, van Hoek, M, Weedon, MN, Aulchenko, YS, Voight, BF, Grallert, H, Balkau, B, Bergman, RN, Borch-Johnsen, K, Jørgensen, T, Sparsø, T, Hansen, T , Pedersen, O & GIANT Consortium 2010, 'Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge', Nature Genetics, vol. 42, no. 2, pp. 142-8. https://doi.org/10.1038/ng.521

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title = "Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge",

abstract = "Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, Β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10 15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10 17; ratio of insulin to glucose area under the curve, P = 1.3 × 10 16) and diminished incretin effect (n = 804; P = 4.3 × 10 4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10 16), VPS13C (rs17271305, P = 4.1 × 10 8), GCKR (rs1260326, P = 7.1 × 10 11) and TCF7L2 (rs7903146, P = 4.2 × 10 10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 × 10 18).",

keywords = "Adenylate Cyclase, Body Mass Index, Denmark, Diabetes Mellitus, Type 2, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Loci, Genetic Variation, Genome-Wide Association Study, Glucose, Glucose Tolerance Test, Humans, Incretins, Insulin, Male, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Proteins, RNA, Messenger, Receptors, Gastrointestinal Hormone",

author = "Richa Saxena and Marie-France Hivert and Claudia Langenberg and Toshiko Tanaka and Pankow, {James S} and Peter Vollenweider and Valeriya Lyssenko and Nabila Bouatia-Naji and Jos{\'e}e Dupuis and Jackson, {Anne U} and Kao, {W H Linda} and Man Li and Glazer, {Nicole L} and Manning, {Alisa K} and Jian'an Luan and Stringham, {Heather M} and Inga Prokopenko and Toby Johnson and Niels Grarup and Boesgaard, {Trine W} and C{\'e}cile Lecoeur and Peter Shrader and Jeffrey O'Connell and Erik Ingelsson and Couper, {David J} and Kenneth Rice and Kijoung Song and Andreasen, {Camilla H} and Christian Dina and Anna K{\"o}ttgen and {Le Bacquer}, Olivier and Fran{\c c}ois Pattou and Jalal Taneera and Valgerdur Steinthorsdottir and Denis Rybin and Kristin Ardlie and Michael Sampson and Lu Qi and {van Hoek}, Mandy and Weedon, {Michael N} and Aulchenko, {Yurii S} and Voight, {Benjamin F} and Harald Grallert and Beverley Balkau and Bergman, {Richard N} and Knut Borch-Johnsen and Torben J{\o}rgensen and Thomas Spars{\o} and Torben Hansen and Oluf Pedersen and {GIANT Consortium}",

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doi = "10.1038/ng.521",

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TY - JOUR

T1 - Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

AU - Saxena, Richa

AU - Hivert, Marie-France

AU - Langenberg, Claudia

AU - Tanaka, Toshiko

AU - Pankow, James S

AU - Vollenweider, Peter

AU - Lyssenko, Valeriya

AU - Bouatia-Naji, Nabila

AU - Dupuis, Josée

AU - Jackson, Anne U

AU - Kao, W H Linda

AU - Li, Man

AU - Glazer, Nicole L

AU - Manning, Alisa K

AU - Luan, Jian'an

AU - Stringham, Heather M

AU - Prokopenko, Inga

AU - Johnson, Toby

AU - Grarup, Niels

AU - Boesgaard, Trine W

AU - Lecoeur, Cécile

AU - Shrader, Peter

AU - O'Connell, Jeffrey

AU - Ingelsson, Erik

AU - Couper, David J

AU - Rice, Kenneth

AU - Song, Kijoung

AU - Andreasen, Camilla H

AU - Dina, Christian

AU - Köttgen, Anna

AU - Le Bacquer, Olivier

AU - Pattou, François

AU - Taneera, Jalal

AU - Steinthorsdottir, Valgerdur

AU - Rybin, Denis

AU - Ardlie, Kristin

AU - Sampson, Michael

AU - Qi, Lu

AU - van Hoek, Mandy

AU - Weedon, Michael N

AU - Aulchenko, Yurii S

AU - Voight, Benjamin F

AU - Grallert, Harald

AU - Balkau, Beverley

AU - Bergman, Richard N

AU - Borch-Johnsen, Knut

AU - Jørgensen, Torben

AU - Sparsø, Thomas

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - GIANT Consortium

PY - 2010/2/1

Y1 - 2010/2/1

N2 - Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, Β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10 15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10 17; ratio of insulin to glucose area under the curve, P = 1.3 × 10 16) and diminished incretin effect (n = 804; P = 4.3 × 10 4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10 16), VPS13C (rs17271305, P = 4.1 × 10 8), GCKR (rs1260326, P = 7.1 × 10 11) and TCF7L2 (rs7903146, P = 4.2 × 10 10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 × 10 18).

AB - Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, Β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10 15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10 17; ratio of insulin to glucose area under the curve, P = 1.3 × 10 16) and diminished incretin effect (n = 804; P = 4.3 × 10 4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10 16), VPS13C (rs17271305, P = 4.1 × 10 8), GCKR (rs1260326, P = 7.1 × 10 11) and TCF7L2 (rs7903146, P = 4.2 × 10 10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 × 10 18).

KW - Adenylate Cyclase

KW - Body Mass Index

KW - Denmark

KW - Diabetes Mellitus, Type 2

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Genetic Loci

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Glucose

KW - Glucose Tolerance Test

KW - Humans

KW - Incretins

KW - Insulin

KW - Male

KW - Meta-Analysis as Topic

KW - Polymorphism, Single Nucleotide

KW - Proteins

KW - RNA, Messenger

KW - Receptors, Gastrointestinal Hormone

U2 - 10.1038/ng.521

DO - 10.1038/ng.521

M3 - Journal article

C2 - 20081857

SN - 1061-4036

VL - 42

SP - 142

EP - 148

JO - Nature: New biology

JF - Nature: New biology

IS - 2

ER -

Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Abstract

Keywords

UN SDGs

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