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, Josee 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. BoesgaardCecile 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, Francois 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, Alex Doney, Colin N. A. Palmer, Andrew D. Morris, GIANT Consortium, MAGIC Investigators

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

    Keywords

    • FASTING PLASMA-GLUCOSE
    • GASTRIC-INHIBITORY POLYPEPTIDE
    • GLUCAGON-LIKE PEPTIDE-1
    • BETA-CELL FUNCTION
    • ASSOCIATION
    • RISK
    • RECEPTOR
    • SENSITIVITY
    • EXPRESSION
    • VARIANTS

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