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

GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, Wellcome Trust Case Control Consortium 2, 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 Craddock, Panos 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, MAGIC investigators, 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, GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, Wellcome Trust Case Control Consortium 2, 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 Craddock, Panos 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, MAGIC investigators, 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

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 × 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.

Figures

Figure 1
Figure 1
Regional association plots around the ATM locus for the logistic regression analysis. The solid and open triangles are from directly typed and imputed SNPs respectively
Figure 2
Figure 2
Effect of KU-55933 on AMPK activation by metformin H4IIE cells were pre-treated with or without 10 μM KU-55933 for 30 min and then with various concentrations of metformin for 1 hr, and AMPK activity measured; Results are mean ± S.D. (n = 2); **significantly different from incubation without KU-55933 by 2-way ANOVA (p

Figure 3

A Western Blot comparing the…

Figure 3

A Western Blot comparing the phosphorylation status of Thr-172 of AMPK and Ser-79…

Figure 3
A Western Blot comparing the phosphorylation status of Thr-172 of AMPK and Ser-79 of ACC (a well characterized marker of AMPK activation). H4IIE cells were pre-treated with or without 10 μM KU-55933 (KU) for 1 hour and then for 3 hours with or without 2.5mmol/L metformin. Metformin induced phosphorylation of AMPK and subsequent phosphorylation of ACC was partially reduced by KU-55933.
Figure 3
Figure 3
A Western Blot comparing the phosphorylation status of Thr-172 of AMPK and Ser-79 of ACC (a well characterized marker of AMPK activation). H4IIE cells were pre-treated with or without 10 μM KU-55933 (KU) for 1 hour and then for 3 hours with or without 2.5mmol/L metformin. Metformin induced phosphorylation of AMPK and subsequent phosphorylation of ACC was partially reduced by KU-55933.

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