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Nat Genet DOI:10.1038/ng.521

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

Publication TypeJournal Article
Year of Publication2010
AuthorsSaxena, R, Hivert, M-F, Langenberg, C, Tanaka, T, Pankow, JS, Vollenweider, P, Lyssenko, V, Bouatia-Naji, N, Dupuis, J, Jackson, AU, Kao, WHLinda, Li, M, Glazer, NL, Manning, AK, Luan, J'an, Stringham, HM, Prokopenko, I, Johnson, T, Grarup, N, Boesgaard, TW, Lecoeur, C, Shrader, P, O'Connell, J, Ingelsson, E, Couper, DJ, Rice, K, Song, K, Andreasen, CH, Dina, C, Köttgen, A, Le Bacquer, O, Pattou, F, Taneera, J, Steinthorsdottir, V, Rybin, D, Ardlie, K, Sampson, M, Qi, L, van Hoek, M, 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, Y-DIda, 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, Palmer, CNA, Pakyz, R, Pascoe, L, Payne, F, Pearson, D, Rathmann, W, Sandbaek, A, Sayer, AAihie, 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, JHua, Illig, T, H Wichmann, E, Wilson, JF, van Duijn, C, Hu, FB, Morris, AD, Frayling, TM, Hattersley, AT, Thorsteinsdottir, U, Stefansson, K, Nilsson, P, Syvänen, A-C, 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
Corporate AuthorsGIANT Consortium, MAGIC Investigators
JournalNat Genet
Volume42
Issue2
Pages142-8
Date Published2010 Feb
ISSN1546-1718
KeywordsAdenylyl Cyclases, 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, Receptors, Gastrointestinal Hormone, RNA, Messenger
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)).

URLhttp://dx.doi.org/10.1038/ng.521
DOI10.1038/ng.521
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/20081857?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID20081857
PubMed Central IDPMC2922003
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