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, 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 A Palmer, 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, 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 journalJournal articleResearchpeer-review

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, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 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 x 10(-18)).
Original languageEnglish
JournalNature Genetics
Volume42
Issue number2
Pages (from-to)142-8
Number of pages6
ISSN1061-4036
DOIs
Publication statusPublished - 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

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