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

Nature Genetics volume 43, pages 117–120 (2011)Cite this article

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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.

Author information

Author notes

  1. Kaixin Zhou, Celine Bellenguez and Mark I McCarthy: These authors contributed equally to this work.

  2. Colin N A Palmer, Peter Donnelly and Ewan R Pearson: These authors jointly directed this work.

Authors and Affiliations

  1. Biomedical Research Institute, University of Dundee, Dundee, UK

    Kaixin Zhou, Roger Tavendale, Louise A Donnelly, Chris Schofield, Lindsay Burch, Fiona Carr, Helen Colhoun, Andrew D Morris, Calum Sutherland, Colin N A Palmer & Ewan R Pearson

  2. UK Wellcome Trust Centre for Human Genetics, Oxford, UK

    Celine Bellenguez, Chris C A Spencer, Amy Strange, Colin Freeman, Anna Rautanen, Mark I McCarthy & Peter Donnelly

  3. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

    Amanda J Bennett, Ruth L Coleman, Christopher J Groves, Mark I McCarthy & Rury R Holman

  4. Diabetes Trials Unit, University of Oxford, Oxford, UK

    Ruth L Coleman & Rury R Holman

  5. College of Life Sciences, University of Dundee, Dundee, UK

    Simon A Hawley & D Grahame Hardie

  6. Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Subiaco, Western Australia, Australia

    Jenefer M Blackwell

  7. Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK

    Jenefer M Blackwell

  8. Department of Psychosis Studies, National Institute for Health Research Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London, London, UK

    Elvira Bramon

  9. The South London and Maudsley National Health Service Foundation Trust, Denmark Hill, London, UK

    Elvira Bramon

  10. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia

    Matthew A Brown

  11. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

    Juan P Casas

  12. Department of Epidemiology and Public Health, University College London, London, UK

    Juan P Casas

  13. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland

    Aiden Corvin

  14. Department of Psychological Medicine, Cardiff University School of Medicine, Heath Park, Cardiff, UK

    Nicholas Craddock

  15. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    Panos Deloukas, Serge Dronov, Sarah Edkins, Emma Gray, Sarah Hunt, Cordelia Langford & Leena Peltonen

  16. Molecular and Physiological Sciences, The Wellcome Trust, London, UK

    Audrey Duncanson

  17. Centre for Digestive Diseases, Queen Mary University of London, London, UK

    Janusz Jankowski

  18. Digestive Diseases Centre, Leicester Royal Infirmary, Leicester, UK

    Janusz Jankowski

  19. Department of Clinical Pharmacology, Old Road Campus, University of Oxford, Oxford, UK

    Janusz Jankowski

  20. Clinical Neurosciences, St George's University of London, London, UK

    Hugh S Markus

  21. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK

    Christopher G Mathew & Richard Trembath

  22. King's College London Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Denmark Hill, London, UK.,

    Robert Plomin

  23. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

    Stephen J Sawcer

  24. Department of Cardiovascular Science, University of Leicester, Glenfield Hospital, Leicester, UK

    Nilesh J Samani

  25. National Institute for Health Research Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital National Health Service Foundation Trust, London, UK

    Ananth C Viswanathan

  26. University College London Institute of Ophthalmology,, London, UK

    Ananth C Viswanathan

  27. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK

    Nicholas W Wood

  28. Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK

    Lorna W Harries & Andrew T Hattersley

  29. Ninewells Hospital and Medical School, Dundee, UK

    Alex S F Doney

  30. UK Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, UK

    Mark I McCarthy

  31. Department of Statistics, University of Oxford, Oxford, UK

    Peter Donnelly

Consortia

The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group

  • 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

The Wellcome Trust Case Control Consortium 2

Contributions

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.

Corresponding author

Correspondence to Ewan R Pearson.

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The author declare no competing financial interests.

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A full list of authors and affiliations is provided at the end of the paper. A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Supplementary Tables 1–6, Supplementary Figures 1–3 and Supplementary Note. (PDF 598 kb)

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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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