Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge by Saxena Richa, Hivert Marie-France, Langenberg Claudia, Tanaka Toshiko, Pankow James S, Vollenweider Peter, Lyssenko Valeriya, Bouatia-Naji Nabila, Dupuis Josée, Jackson Anne U, Kao W H Linda, Li Man, Glazer Nicole L, Manning Alisa K, Luan Jian'an, Stringham Heather M, Prokopenko Inga, Johnson Toby, Grarup Niels, Boesgaard Trine W, Lecoeur Cécile, Shrader Peter, O'Connell Jeffrey, Ingelsson Erik, Couper David J, Rice Kenneth, Song Kijoung, Andreasen Camilla H, Dina Christian, Köttgen Anna, Le Bacquer Olivier, Pattou François, Taneera Jalal, Steinthorsdottir Valgerdur, Rybin Denis, Ardlie Kristin, Sampson Michael, Qi Lu, van Hoek Mandy, Weedon Michael N, Aulchenko Yurii S, Voight Benjamin F, Grallert Harald, Balkau Beverley, Bergman Richard N, Bielinski Suzette J, Bonnefond Amelie, Bonnycastle Lori L, Borch-Johnsen Knut, Böttcher Yvonne, Brunner Eric, Buchanan Thomas A, Bumpstead Suzannah J, Cavalcanti-Proença Christine, Charpentier Guillaume, Chen Yii-Der Ida, Chines Peter S, Collins Francis S, Cornelis Marilyn, J Crawford Gabriel, Delplanque Jerome, Doney Alex, Egan Josephine M, Erdos Michael R, Firmann Mathieu, Forouhi Nita G, Fox Caroline S, Goodarzi Mark O, Graessler Jürgen, Hingorani Aroon, Isomaa Bo, Jørgensen Torben, Kivimaki Mika, Kovacs Peter, Krohn Knut, Kumari Meena, Lauritzen Torsten, Lévy-Marchal Claire, Mayor Vladimir, McAteer Jarred B, Meyre David, Mitchell Braxton D, Mohlke Karen L, Morken Mario A, Narisu Narisu, Palmer Colin N A, Pakyz Ruth, Pascoe Laura, Payne Felicity, Pearson Daniel, Rathmann Wolfgang, Sandbaek Annelli, Sayer Avan Aihie, Scott Laura J, Sharp Stephen J, Sijbrands Eric, Singleton Andrew, Siscovick David S, Smith Nicholas L, Sparsø Thomas, Swift Amy J, Syddall Holly, Thorleifsson Gudmar, Tönjes Anke, Tuomi Tiinamaija, Tuomilehto Jaakko, Valle Timo T, Waeber Gérard, Walley Andrew, Waterworth Dawn M, Zeggini Eleftheria, Zhao Jing Hua, GIANT consortium, MAGIC investigators, Illig Thomas, Wichmann H Erich, Wilson James F, van Duijn Cornelia, Hu Frank B, Morris Andrew D, Frayling Timothy M, Hattersley Andrew T, Thorsteinsdottir Unnur, Stefansson Kari, Nilsson Peter, Syvänen Ann-Christine, Shuldiner Alan R, Walker Mark, Bornstein Stefan R, Schwarz Peter, Williams Gordon H, Nathan David M, Kuusisto Johanna, Laakso Markku, Cooper Cyrus, Marmot Michael, Ferrucci Luigi, Mooser Vincent, Stumvoll Michael, Loos Ruth J F, Altshuler David, Psaty Bruce M, Rotter Jerome I, Boerwinkle Eric, Hansen Torben, Pedersen Oluf, Florez Jose C, McCarthy Mark I, Boehnke Michael, Barroso Inês, Sladek Robert, Froguel Philippe, Meigs James B, Groop Leif, Wareham Nicholas J, Watanabe Richard M in Nature genetics (2010). PubMed

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)).

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