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 Anluan; Heather M. Stringham; Inga Prokopenko; Toby Johnson; Niels Grarup; Trine W. Boesgaard; Cécile Lecoeur; Peter Shrader; Jeffrey Oconnell; 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; Suzette J. Bielinski; Amelie Bonnefond; Lori L. Bonnycastle; Knut Borch-Johnsen; Yvonne BöTTCHER; Eric Brunner; Thomas A. Buchanan; Suzannah J. Bumpstead; Christine Cavalcanti-Proença; Guillaume Charpentier; Yii Der Ida Chen; Peter S. Chines; Francis S. Collins; Marilyn Cornelis; Gabriel J. Crawford; Jerome Delplanque; Alex Doney; Josephine M. Egan; Michael R. Erdos; Mathieu Firmann; Nita G. Forouhi; Caroline S. Fox; Mark O. Goodarzi; Jürgen Graessler; Aroon Hingorani; Bo Isomaa; Torben Jørgensen; Mika Kivimaki; Peter Kovacs; Knut Krohn; Meena Kumari; Torsten Lauritzen; Claire Lévy-Marchal; Vladimir Mayor; Jarred B. McAteer; David Meyre; Braxton D. Mitchell; Karen L. Mohlke; Mario A. Morken; Narisu Narisu; Colin N. Apalmer; Ruth Pakyz; Laura Pascoe; Felicity Payne; Daniel Pearson; Wolfgang Rathmann; Annelli Sandbaek; Avan Aihie Sayer; Laura J. Scott; Stephen J. Sharp; Eric Sijbrands; Andrew Singleton; David S. Siscovick; Nicholas L. Smith; Thomas Sparsø; Amy J. Swift; Holly Syddall; Gudmar Thorleifsson; Anke TöNJES; Tiinamaija Tuomi; Jaakko Tuomilehto; Timo T. Valle; Gérard Waeber; Andrew Walley; Dawn M. Waterworth; Eleftheria Zeggini; Jing Hua Zhao; Giant Consortium; Thomas Illig; H. Erich Wichmann; James F. Wilson; Cornelia Van Duijn; Frank B. Hu; Andrew D. Morris; Timothy M. Frayling; Andrew T. Hattersley; Unnur Thorsteinsdottir; Kari Stefansson; Peter Nilsson; Ann Christine Syvänen; Alan R. Shuldiner; Mark Walker; Stefan R. Bornstein; Peter Schwarz; Gordon H. Williams; David M. Nathan; Johanna Kuusisto; Markku Laakso; Cyrus Cooper; Michael Marmot; Luigi Ferrucci; Vincent Mooser; Michael Stumvoll; Ruth J.F. Loos; David Altshuler; Bruce M. Psaty; Jerome I. Rotter; Eric Boerwinkle; Torben Hansen; Oluf Pedersen; Jose C. Florez; Mark I. McCarthy; Michael Boehnke; Inês Barroso; Robert Sladek; Philippe Froguel; James B. Meigs; Leif Groop; Nicholas J. Wareham; Richard M. Watanabe

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 Anluan, Heather M. Stringham, Inga Prokopenko, Toby Johnson, Niels Grarup, Trine W. BoesgaardCécile Lecoeur, Peter Shrader, Jeffrey Oconnell, 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, Suzette J. Bielinski, Amelie Bonnefond, Lori L. Bonnycastle, Knut Borch-Johnsen, Yvonne BöTTCHER, Eric Brunner, Thomas A. Buchanan, Suzannah J. Bumpstead, Christine Cavalcanti-Proença, Guillaume Charpentier, Yii Der Ida Chen, Peter S. Chines, Francis S. Collins, Marilyn Cornelis, Gabriel J. Crawford, Jerome Delplanque, Alex Doney, Josephine M. Egan, Michael R. Erdos, Mathieu Firmann, Nita G. Forouhi, Caroline S. Fox, Mark O. Goodarzi, Jürgen Graessler, Aroon Hingorani, Bo Isomaa, Torben Jørgensen, Mika Kivimaki, Peter Kovacs, Knut Krohn, Meena Kumari, Torsten Lauritzen, Claire Lévy-Marchal, Vladimir Mayor, Jarred B. McAteer, David Meyre, Braxton D. Mitchell, Karen L. Mohlke, Mario A. Morken, Narisu Narisu, Colin N. Apalmer, Ruth Pakyz, Laura Pascoe, Felicity Payne, Daniel Pearson, Wolfgang Rathmann, Annelli Sandbaek, Avan Aihie Sayer, Laura J. Scott, Stephen J. Sharp, Eric Sijbrands, Andrew Singleton, David S. Siscovick, Nicholas L. Smith, Thomas Sparsø, Amy J. Swift, Holly Syddall, Gudmar Thorleifsson, Anke TöNJES, Tiinamaija Tuomi, Jaakko Tuomilehto, Timo T. Valle, Gérard Waeber, Andrew Walley, Dawn M. Waterworth, Eleftheria Zeggini, Jing Hua Zhao, Giant Consortium, Thomas Illig, H. Erich Wichmann, James F. Wilson, Cornelia Van Duijn, Frank B. Hu, Andrew D. Morris, Timothy M. Frayling, Andrew T. Hattersley, Unnur Thorsteinsdottir, Kari Stefansson, Peter Nilsson, Ann Christine Syvänen, Alan R. Shuldiner, Mark Walker, Stefan R. Bornstein, Peter Schwarz, Gordon H. Williams, David M. Nathan, Johanna Kuusisto, Markku Laakso, Cyrus Cooper, Michael Marmot, Luigi Ferrucci, Vincent Mooser, Michael Stumvoll, Ruth J.F. Loos, David Altshuler, Bruce M. Psaty, Jerome I. Rotter, Eric Boerwinkle, Torben Hansen, Oluf Pedersen, Jose C. Florez, Mark I. McCarthy, Michael Boehnke, Inês Barroso, Robert Sladek, Philippe Froguel, James B. Meigs, Leif Groop, Nicholas J. Wareham, Richard M. Watanabe

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

468 Scopus citations

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 (US)
Pages (from-to)	142-148
Number of pages	7
Journal	Nature Genetics
Volume	42
Issue number	2
DOIs	https://doi.org/10.1038/ng.521
State	Published - Feb 2010

ASJC Scopus subject areas

Genetics

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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., Anluan, J., Stringham, H. M., Prokopenko, I., Johnson, T., Grarup, N., ... Watanabe, R. M. (2010). Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nature Genetics, 42(2), 142-148. https://doi.org/10.1038/ng.521

Saxena, R, Hivert, MF, 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, Anluan, J, Stringham, HM, Prokopenko, I, Johnson, T, Grarup, N, Boesgaard, TW, Lecoeur, C, Shrader, P, Oconnell, J, Ingelsson, E, Couper, DJ, Rice, K, Song, K, Andreasen, CH, Dina, C, KöTTGEN, A, Bacquer, OL, Pattou, F, Taneera, J, Steinthorsdottir, V, Rybin, D, Ardlie, K, Sampson, M, Qi, L, Hoek, MV, Weedon, MN, Aulchenko, YS, Voight, BF, Grallert, H, Balkau, B, Bergman, RN, Bielinski, SJ, Bonnefond, A, Bonnycastle, LL, Borch-Johnsen, K, BöTTCHER, Y, Brunner, E, Buchanan, TA, Bumpstead, SJ, Cavalcanti-Proença, C, Charpentier, G, Chen, YDI, Chines, PS, Collins, FS, Cornelis, M, Crawford, GJ, Delplanque, J, Doney, A, Egan, JM, Erdos, MR, Firmann, M, Forouhi, NG, Fox, CS, Goodarzi, MO, Graessler, J, Hingorani, A, Isomaa, B, Jørgensen, T, Kivimaki, M, Kovacs, P, Krohn, K, Kumari, M, Lauritzen, T, Lévy-Marchal, C, Mayor, V, McAteer, JB, Meyre, D, Mitchell, BD, Mohlke, KL, Morken, MA, Narisu, N, Apalmer, CN, Pakyz, R, Pascoe, L, Payne, F, Pearson, D, Rathmann, W, Sandbaek, A, Sayer, AA, Scott, LJ, Sharp, SJ, Sijbrands, E, Singleton, A, Siscovick, DS, Smith, NL, Sparsø, T, Swift, AJ, Syddall, H, Thorleifsson, G, TöNJES, A, Tuomi, T, Tuomilehto, J, Valle, TT, Waeber, G, Walley, A, Waterworth, DM, Zeggini, E, Zhao, JH, Consortium, G, Illig, T, Wichmann, HE, Wilson, JF, Duijn, CV, Hu, FB, Morris, AD, Frayling, TM, Hattersley, AT, Thorsteinsdottir, U, Stefansson, K, Nilsson, P, Syvänen, AC, Shuldiner, AR, Walker, M, Bornstein, SR, Schwarz, P, Williams, GH, Nathan, DM, Kuusisto, J, Laakso, M, Cooper, C, Marmot, M, Ferrucci, L, Mooser, V, Stumvoll, M, Loos, RJF, Altshuler, D, Psaty, BM, Rotter, JI, Boerwinkle, E, Hansen, T, Pedersen, O, Florez, JC, McCarthy, MI, Boehnke, M, Barroso, I, Sladek, R, Froguel, P, Meigs, JB, Groop, L, Wareham, NJ & Watanabe, RM 2010, 'Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge', Nature Genetics, vol. 42, no. 2, pp. 142-148. https://doi.org/10.1038/ng.521

@article{f504541a4d2d4a17a6e94e11ba14a6f3,

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).",

author = "Richa Saxena and Hivert, {Marie France} 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 Anluan 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 Oconnell 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 Bacquer, {Olivier Le} 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 Hoek, {Mandy Van} and Weedon, {Michael N.} and Aulchenko, {Yurii S.} and Voight, {Benjamin F.} and Harald Grallert and Beverley Balkau and Bergman, {Richard N.} and Bielinski, {Suzette J.} and Amelie Bonnefond and Bonnycastle, {Lori L.} and Knut Borch-Johnsen and Yvonne B{\"o}TTCHER and Eric Brunner and Buchanan, {Thomas A.} and Bumpstead, {Suzannah J.} and Christine Cavalcanti-Proen{\c c}a and Guillaume Charpentier and Chen, {Yii Der Ida} and Chines, {Peter S.} and Collins, {Francis S.} and Marilyn Cornelis and Crawford, {Gabriel J.} and Jerome Delplanque and Alex Doney and Egan, {Josephine M.} and Erdos, {Michael R.} and Mathieu Firmann and Forouhi, {Nita G.} and Fox, {Caroline S.} and Goodarzi, {Mark O.} and J{\"u}rgen Graessler and Aroon Hingorani and Bo Isomaa and Torben J{\o}rgensen and Mika Kivimaki and Peter Kovacs and Knut Krohn and Meena Kumari and Torsten Lauritzen and Claire L{\'e}vy-Marchal and Vladimir Mayor and McAteer, {Jarred B.} and David Meyre and Mitchell, {Braxton D.} and Mohlke, {Karen L.} and Morken, {Mario A.} and Narisu Narisu and Apalmer, {Colin N.} and Ruth Pakyz and Laura Pascoe and Felicity Payne and Daniel Pearson and Wolfgang Rathmann and Annelli Sandbaek and Sayer, {Avan Aihie} and Scott, {Laura J.} and Sharp, {Stephen J.} and Eric Sijbrands and Andrew Singleton and Siscovick, {David S.} and Smith, {Nicholas L.} and Thomas Spars{\o} and Swift, {Amy J.} and Holly Syddall and Gudmar Thorleifsson and Anke T{\"o}NJES and Tiinamaija Tuomi and Jaakko Tuomilehto and Valle, {Timo T.} and G{\'e}rard Waeber and Andrew Walley and Waterworth, {Dawn M.} and Eleftheria Zeggini and Zhao, {Jing Hua} and Giant Consortium and Thomas Illig and Wichmann, {H. Erich} and Wilson, {James F.} and Duijn, {Cornelia Van} and Hu, {Frank B.} and Morris, {Andrew D.} and Frayling, {Timothy M.} and Hattersley, {Andrew T.} and Unnur Thorsteinsdottir and Kari Stefansson and Peter Nilsson and Syv{\"a}nen, {Ann Christine} and Shuldiner, {Alan R.} and Mark Walker and Bornstein, {Stefan R.} and Peter Schwarz and Williams, {Gordon H.} and Nathan, {David M.} and Johanna Kuusisto and Markku Laakso and Cyrus Cooper and Michael Marmot and Luigi Ferrucci and Vincent Mooser and Michael Stumvoll and Loos, {Ruth J.F.} and David Altshuler and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Eric Boerwinkle and Torben Hansen and Oluf Pedersen and Florez, {Jose C.} and McCarthy, {Mark I.} and Michael Boehnke and In{\^e}s Barroso and Robert Sladek and Philippe Froguel and Meigs, {James B.} and Leif Groop and Wareham, {Nicholas J.} and Watanabe, {Richard M.}",

year = "2010",

month = feb,

doi = "10.1038/ng.521",

language = "English (US)",

volume = "42",

pages = "142--148",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

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 - Anluan, Jian

AU - Stringham, Heather M.

AU - Prokopenko, Inga

AU - Johnson, Toby

AU - Grarup, Niels

AU - Boesgaard, Trine W.

AU - Lecoeur, Cécile

AU - Shrader, Peter

AU - Oconnell, 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 - Bacquer, Olivier Le

AU - Pattou, François

AU - Taneera, Jalal

AU - Steinthorsdottir, Valgerdur

AU - Rybin, Denis

AU - Ardlie, Kristin

AU - Sampson, Michael

AU - Qi, Lu

AU - Hoek, Mandy Van

AU - Weedon, Michael N.

AU - Aulchenko, Yurii S.

AU - Voight, Benjamin F.

AU - Grallert, Harald

AU - Balkau, Beverley

AU - Bergman, Richard N.

AU - Bielinski, Suzette J.

AU - Bonnefond, Amelie

AU - Bonnycastle, Lori L.

AU - Borch-Johnsen, Knut

AU - BöTTCHER, Yvonne

AU - Brunner, Eric

AU - Buchanan, Thomas A.

AU - Bumpstead, Suzannah J.

AU - Cavalcanti-Proença, Christine

AU - Charpentier, Guillaume

AU - Chen, Yii Der Ida

AU - Chines, Peter S.

AU - Collins, Francis S.

AU - Cornelis, Marilyn

AU - Crawford, Gabriel J.

AU - Delplanque, Jerome

AU - Doney, Alex

AU - Egan, Josephine M.

AU - Erdos, Michael R.

AU - Firmann, Mathieu

AU - Forouhi, Nita G.

AU - Fox, Caroline S.

AU - Goodarzi, Mark O.

AU - Graessler, Jürgen

AU - Hingorani, Aroon

AU - Isomaa, Bo

AU - Jørgensen, Torben

AU - Kivimaki, Mika

AU - Kovacs, Peter

AU - Krohn, Knut

AU - Kumari, Meena

AU - Lauritzen, Torsten

AU - Lévy-Marchal, Claire

AU - Mayor, Vladimir

AU - McAteer, Jarred B.

AU - Meyre, David

AU - Mitchell, Braxton D.

AU - Mohlke, Karen L.

AU - Morken, Mario A.

AU - Narisu, Narisu

AU - Apalmer, Colin N.

AU - Pakyz, Ruth

AU - Pascoe, Laura

AU - Payne, Felicity

AU - Pearson, Daniel

AU - Rathmann, Wolfgang

AU - Sandbaek, Annelli

AU - Sayer, Avan Aihie

AU - Scott, Laura J.

AU - Sharp, Stephen J.

AU - Sijbrands, Eric

AU - Singleton, Andrew

AU - Siscovick, David S.

AU - Smith, Nicholas L.

AU - Sparsø, Thomas

AU - Swift, Amy J.

AU - Syddall, Holly

AU - Thorleifsson, Gudmar

AU - TöNJES, Anke

AU - Tuomi, Tiinamaija

AU - Tuomilehto, Jaakko

AU - Valle, Timo T.

AU - Waeber, Gérard

AU - Walley, Andrew

AU - Waterworth, Dawn M.

AU - Zeggini, Eleftheria

AU - Zhao, Jing Hua

AU - Consortium, Giant

AU - Illig, Thomas

AU - Wichmann, H. Erich

AU - Wilson, James F.

AU - Duijn, Cornelia Van

AU - Hu, Frank B.

AU - Morris, Andrew D.

AU - Frayling, Timothy M.

AU - Hattersley, Andrew T.

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Nilsson, Peter

AU - Syvänen, Ann Christine

AU - Shuldiner, Alan R.

AU - Walker, Mark

AU - Bornstein, Stefan R.

AU - Schwarz, Peter

AU - Williams, Gordon H.

AU - Nathan, David M.

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Cooper, Cyrus

AU - Marmot, Michael

AU - Ferrucci, Luigi

AU - Mooser, Vincent

AU - Stumvoll, Michael

AU - Loos, Ruth J.F.

AU - Altshuler, David

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Boerwinkle, Eric

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Florez, Jose C.

AU - McCarthy, Mark I.

AU - Boehnke, Michael

AU - Barroso, Inês

AU - Sladek, Robert

AU - Froguel, Philippe

AU - Meigs, James B.

AU - Groop, Leif

AU - Wareham, Nicholas J.

AU - Watanabe, Richard M.

PY - 2010/2

Y1 - 2010/2

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).

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U2 - 10.1038/ng.521

DO - 10.1038/ng.521

M3 - Article

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SN - 1061-4036

VL - 42

SP - 142

EP - 148

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

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