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 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; 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

doi:10.1038/ng.735

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

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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 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 language	English
Pages (from-to)	117 - U57
Number of pages	4
Journal	Nature Genetics
Volume	43
Issue number	2
DOIs	https://doi.org/10.1038/ng.735
Publication status	Published - Feb 2011

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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., ... Pearson, E. R. (2011). Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature Genetics, 43(2), 117 - U57. https://doi.org/10.1038/ng.735

@article{0f5d788e1a4a45c386a171aba3be7e18,

title = "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 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.",

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

year = "2011",

month = feb,

doi = "10.1038/ng.735",

language = "English",

volume = "43",

pages = "117 -- U57",

journal = "Nature Genetics",

issn = "1546-1718",

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Zhou, K, Bellenguez, C, Spencer, CCA, Bennett, AJ, Coleman, RL, Tavendale, R, Hawley, SA, Donnelly, LA, Schofield, C, Groves, CJ, Burch, L, Carr, F, Strange, A, Freeman, C, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Craddock, N, Deloukas, P, Dronov, S, Duncanson, A, Edkins, S, Gray, E, Hunt, S, Jankowski, J, Langford, C, Markus, HS, Mathew, CG , Plomin, R, Rautanen, A, Sawcer, SJ, Samani, NJ, Trembath, R, Viswanathan, AC, Wood, NW, Harries, LW, Hattersley, AT, Doney, ASF, Colhoun, H, Morris, AD, Sutherland, C, Hardie, DG, Peltonen, L, McCarthy, MI, Holman, RR, Palmer, CNA, Donnelly, P & Pearson, ER 2011, 'Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes', Nature Genetics, vol. 43, no. 2, pp. 117 - U57. https://doi.org/10.1038/ng.735

TY - JOUR

T1 - Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

AU - Zhou, Kaixin

AU - Bellenguez, Celine

AU - Spencer, Chris C. A.

AU - Bennett, Amanda J.

AU - Coleman, Ruth L.

AU - Tavendale, Roger

AU - Hawley, Simon A.

AU - Donnelly, Louise A.

AU - Schofield, Chris

AU - Groves, Christopher J.

AU - Burch, Lindsay

AU - Carr, Fiona

AU - Strange, Amy

AU - Freeman, Colin

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Craddock, Nicholas

AU - Deloukas, Panos

AU - Dronov, Serge

AU - Duncanson, Audrey

AU - Edkins, Sarah

AU - Gray, Emma

AU - Hunt, Sarah

AU - Jankowski, Janusz

AU - Langford, Cordelia

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Sawcer, Stephen J.

AU - Samani, Nilesh J.

AU - Trembath, Richard

AU - Viswanathan, Ananth C.

AU - Wood, Nicholas W.

AU - Harries, Lorna W.

AU - Hattersley, Andrew T.

AU - Doney, Alex S. F.

AU - Colhoun, Helen

AU - Morris, Andrew D.

AU - Sutherland, Calum

AU - Hardie, D. Grahame

AU - Peltonen, Leena

AU - McCarthy, Mark I.

AU - Holman, Rury R.

AU - Palmer, Colin N. A.

AU - Donnelly, Peter

AU - Pearson, Ewan R.

PY - 2011/2

Y1 - 2011/2

N2 - 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.

AB - 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.

U2 - 10.1038/ng.735

DO - 10.1038/ng.735

M3 - Article

SN - 1546-1718

VL - 43

SP - 117 - U57

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

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

Abstract

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