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

R Saxena, MF Hivert, C Langenberg, T Tanaka, JS Pankow, P Vollenweider, V Lyssenko, N Bouatia-Naji, J Dupuis, AU Jackson, WHL Kao, M Li, NL Glazer, AK Manning, J Luan, HM Stringham, I Prokopenko, T Johnson, N Grarup, TW BoesgaardC Lecoeur, P Shrader, J O'Connell, E Ingelsson, DJ Couper, K Rice, KJ Song, CH Andreasen, C Dina, A Kottgen, O Le Bacquer, F Pattou, J Taneera, V Steinthorsdottir, D Rybin, K Ardlie, M Sampson, L Qi, Mandy van Hoek, MN Weedon, YS Aulchenko, BF Voight, H Grallert, B Balkau, RN Bergman, SJ Bielinski, A Bonnefond, LL Bonnycastle, K Borch-Johnsen, Y Boettcher, E Brunner, TA Buchanan, SJ Bumpstead, C Cavalcanti-Proenca, G Charpentier, YDI Chen, PS Chines, FS Collins, M Cornelis, GJ Crawford, J Delplanque, A Doney, JM Egan, MR Erdos, M Firmann, NG Forouhi, CS Fox, MO Goodarzi, J Graessler, A Hingorani, B Isomaa, T Jorgensen, M Kivimaki, P Kovacs, K Krohn, M Kumari, T Lauritzen, C Levy-Marchal, V Mayor, JB McAteer, D Meyre, BD Mitchell, KL Mohlke, MA Morken, N Narisu, CNA Palmer, R Pakyz, L Pascoe, F Payne, D Pearson, W Rathmann, A Sandbaek, AA Sayer, LJ Scott, SJ Sharp, E.J.G. Sijbrands, A Singleton, DS Siscovick, NL Smith, T Sparso, AJ Swift, H Syddall, G Thorleifsson, A Tonjes, T Tuomi, J Tuomilehto, TT Valle, G Waeber, A Walley, DM Waterworth, E Zeggini, JH Zhao, T Illig, HE Wichmann, JF Wilson, Cornelia Duijn, FB Hu, AD Morris, TM Frayling, AT Hattersley, U Thorsteinsdottir, K Stefansson, P Nilsson, AC Syvanen, AR Shuldiner, M Walker, SR Bornstein, P Schwarz, GH Williams, DM Nathan, J Kuusisto, M Laakso, C Cooper, M Marmot, L Ferrucci, V Mooser, M Stumvoll, RJF Loos, D Altshuler, BM Psaty, JI Rotter, E Boerwinkle, T Hansen, O Pedersen, JC Florez, MI McCarthy, M Boehnke, I Barroso, R Sladek, P Froguel, JB Meigs, L Groop, NJ Wareham, RM Watanabe

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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, 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 languageUndefined/Unknown
Pages (from-to)142-U75
JournalNature Genetics
Volume42
Issue number2
DOIs
Publication statusPublished - 2010

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