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

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.

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Figure 1: Regional association plots around the ATM locus for the logistic regression analysis.
Figure 2: Effect of KU-55933 on AMPK activation by metformin.
Figure 3: A protein blot comparing the phosphorylation status of Thr172 of AMPK and Ser79 of ACC (a well characterized marker of AMPK activation).

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Acknowledgements

We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Wellcome Trust provides support for the Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) and informatics support was provided by the Chief Scientist Office. The Wellcome Trust funds the Scottish Health Informatics Programme, provides core support for the Wellcome Trust Centre for Human Genetics in Oxford and funds the Wellcome Trust Case Control Consortium 2. This research was specifically funded by Diabetes UK (07/0003525), MRC (G0601261) and the Wellcome Trust (084726/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z). We also acknowledge support from the National Institute for Health Research award to Moorfields Eye Hospital National Health Service Foundation Trust and University College London Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology (to A.C.V.). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. K.Z. holds a Henry Wellcome Post-Doctoral Fellowship. S.A.H. and D.G.H. were supported by the EXGENESIS consortium (LSHM-CT-2004-005272) funded by the European Commission.

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A.D.M., C.N.A.P., E.R.P., A.S.F.D. H.C., A.T.H. and M.I.M. oversaw cohort collection for GoDARTS. R.R.H., M.I.M., R.L.C. and C.J.G. oversaw cohort collection for the UKPDS. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.D., S.E., E.G., S.H. and C.L.) executed GWAS sample handling, genotyping and quality control. A.J.B., R. Tavendale, L.B., C.J.G. and F.C. performed the replication genotyping. The WTCCC2 Management Committee (P. Donnelly, J.M.B., E.B., M.A.B., J.P.C., A.C., N.C., P. Deloukas, A.D., J.J., H.S.M., C.G.M., R.P., A.R., S.J.S., N.J.S., R. Trembath, A.C.V., L.P. and N.W.W.) monitored the execution of the GWAS. K.Z., C.B., C.C.A.S., L.A.D., A.S. and C.F. performed statistical analyses. K.Z. and L.W.H. performed bioinformatic analyses. S.A.H., D.G.H., C. Schofield and C. Sutherland performed the functional studies. MAGIC investigators provided summary data on glycemic quantitative trait association. K.Z., C.B., C.C.A.S., C.N.P., A.D.M., C. Sutherland, D.G.H., R.R.H., M.I.M., P. Donnelly and E.R.P. contributed to writing the manuscript. All authors reviewed the final manuscript.

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Correspondence to Ewan R Pearson.

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The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group., The Wellcome Trust Case Control Consortium 2. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43, 117–120 (2011). https://doi.org/10.1038/ng.735

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