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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)142-148
Number of pages7
JournalNature Genetics
Volume42
Issue number2
DOIs
StatePublished - Feb 2010

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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