Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Kaixin Zhou, Celine Bellenguez, Chris C. A. Spencer, Amanda J. Bennett, Ruth L. Coleman, Roger Tavendale, Simon A. Hawley, Louise A. Donnelly, Chris Schofield, Christopher J. Groves, Lindsay Burch, Fiona Carr, Amy Strange, Colin Freeman, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Nicholas CraddockPanos Deloukas, Serge Dronov, Audrey Duncanson, Sarah Edkins, Emma Gray, Sarah Hunt, Janusz Jankowski, Cordelia Langford, Hugh S. Markus, Christopher G. Mathew, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Nilesh J. Samani, Richard Trembath, Ananth C. Viswanathan, Nicholas W. Wood, Lorna W. Harries, Andrew T. Hattersley, Alex S.F. Doney, Helen Colhoun, Andrew D. Morris, Calum Sutherland, D. Grahame Hardie, Leena Peltonen, Mark I. McCarthy, Rury R. Holman, Colin N. A. Palmer, Peter Donnelly, Ewan R. Pearson, Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators

    Research output: Contribution to journalLetter

    288 Citations (Scopus)

    Abstract

    Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 x 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.

    Original languageEnglish
    Pages (from-to)117-120
    Number of pages4
    JournalNature Genetics
    Volume43
    Issue number2
    DOIs
    Publication statusPublished - Feb 2011

    Keywords

    • ACTIVATED PROTEIN-KINASE
    • GENOME-WIDE ASSOCIATION
    • ATAXIA-TELANGIECTASIA
    • CANCER
    • CELLS
    • RISK
    • AMPK
    • IDENTIFICATION
    • HOMEOSTASIS
    • REDUCTASE

    Cite this

    Zhou, K., Bellenguez, C., Spencer, C. C. A., Bennett, A. J., Coleman, R. L., Tavendale, R., Hawley, S. A., Donnelly, L. A., Schofield, C., Groves, C. J., Burch, L., Carr, F., Strange, A., Freeman, C., Blackwell, J. M., Bramon, E., Brown, M. A., Casas, J. P., Corvin, A., ... Wellcome Trust Case Control Consor, GoDARTS UKPDS Diabet Pharmacogenet, MAGIC Investigators (2011). Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature Genetics, 43(2), 117-120. https://doi.org/10.1038/ng.735