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

Research output: Contribution to journalArticlepeer-review

365 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 - U57
Number of pages4
JournalNature Genetics
Volume43
Issue number2
DOIs
Publication statusPublished - Feb 2011

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