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

被引：330

作者：

Zhou, Kaixin ^{[1
]}

Bellenguez, Celine ^{[2
]}

Spencer, Chris C. A. ^{[2
]}

Bennett, Amanda J. ^{[3
]}

Coleman, Ruth L. ^{[3
,4
]}

Tavendale, Roger ^{[1
]}

Hawley, Simon A. ^{[5
]}

Donnelly, Louise A. ^{[1
]}

Schofield, Chris ^{[1
]}

Groves, Christopher J. ^{[3
]}

Burch, Lindsay ^{[1
]}

Carr, Fiona ^{[1
]}

Strange, Amy ^{[2
]}

Freeman, Colin ^{[2
]}

Blackwell, Jenefer M. ^{[6
,7
]}

Bramon, Elvira ^{[8
,9
]}

Brown, Matthew A. ^{[10
]}

Casas, Juan P. ^{[11
,12
]}

Corvin, Aiden ^{[13
]}

Craddock, Nicholas ^{[14
]}

Deloukas, Panos ^{[15
]}

Dronov, Serge ^{[15
]}

Duncanson, Audrey ^{[16
]}

Edkins, Sarah ^{[15
]}

Gray, Emma ^{[15
]}

Hunt, Sarah ^{[15
]}

Jankowski, Janusz ^{[17
,18
,19
]}

Langford, Cordelia ^{[15
]}

Markus, Hugh S. ^{[20
]}

Mathew, Christopher G. ^{[21
]}

Plomin, Robert ^{[22
]}

Rautanen, Anna ^{[2
]}

Sawcer, Stephen J. ^{[23
]}

Samani, Nilesh J. ^{[24
]}

Trembath, Richard ^{[21
]}

Viswanathan, Ananth C. ^{[25
,26
]}

Wood, Nicholas W. ^{[27
]}

Harries, Lorna W. ^{[28
]}

Hattersley, Andrew T. ^{[28
]}

Doney, Alex S. F. ^{[29
]}

Colhoun, Helen ^{[1
]}

Morris, Andrew D. ^{[1
]}

Sutherland, Calum ^{[1
]}

Hardie, D. Grahame ^{[5
]}

Peltonen, Leena ^{[15
]}

McCarthy, Mark I. ^{[2
,3
,30
]}

Holman, Rury R. ^{[3
,4
]}

Palmer, Colin N. A. ^{[1
]}

Donnelly, Peter ^{[2
,31
]}

Pearson, Ewan R. ^{[1
]}

机构：

[1] Univ Dundee, Biomed Res Inst, Dundee, Scotland

[2] UK Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[4] Univ Oxford, Diabet Trials Unit, Oxford, England

[5] Univ Dundee, Coll Life Sci, Dundee, Scotland

[6] Univ Western Australia, Ctr Child Hlth Res, Inst Child Hlth Res, Subiaco, WA, Australia

[7] Univ Cambridge, Sch Clin Med, Cambridge Inst Med Res, Cambridge, England

[8] Kings Coll London, Dept Psychosis Studies, Natl Inst Hlth Res, Biomed Res Ctr Mental Hlth,Inst Psychiat, London WC2R 2LS, England

[9] S London & Maudsley Natl Hlth Serv Fdn Trust, London, England

[10] Univ Queensland, Princess Alexandra Hosp, Diamantina Inst Canc Immunol & Metab Med, Brisbane, Qld, Australia

[11] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England

[12] UCL, Dept Epidemiol & Publ Hlth, London, England

[13] Trinity Coll Dublin, Inst Mol Med, Neuropsychiat Genet Res Grp, Dublin, Ireland

[14] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales

[15] Wellcome Trust Sanger Inst, Cambridge, England

[16] Wellcome Trust Res Labs, Mol & Physiol Sci, London, England

[17] Queen Mary Univ London, Ctr Digest Dis, London, England

[18] Leicester Royal Infirm, Ctr Digest Dis, Leicester, Leics, England

[19] Univ Oxford, Dept Clin Pharmacol, Oxford, England

[20] St Georges Univ London, London, England

[21] Kings Coll London, Sch Med, Guys Hosp, Dept Med & Mol Genet, London WC2R 2LS, England

[22] Kings Coll London, Social Genet & Dev Psychiat Ctr, Inst Psychiat, London WC2R 2LS, England

[23] Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Cambridge CB2 2QQ, England

[24] Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England

[25] Moorfields Eye Hosp Natl Hlth Serv Fdn Trust, Natl Inst Hlth Res, Biomed Res Ctr Ophthalmol, London, England

[26] UCL, Inst Ophthalmol, London, England

[27] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[28] Univ Exeter, Peninsula Coll Med & Dent, Exeter, Devon, England

[29] Univ Dundee, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland

[30] Churchill Hosp, UK Oxford Natl Inst Hlth Res, Biomed Res Ctr, Oxford OX3 7LJ, England

[31] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

来源：

NATURE GENETICS | 2011年 / 43卷 / 02期

基金：

英国惠康基金;

关键词：

ACTIVATED PROTEIN-KINASE; GENOME-WIDE ASSOCIATION; ATAXIA-TELANGIECTASIA; CANCER; CELLS; RISK; AMPK; IDENTIFICATION; HOMEOSTASIS; REDUCTASE;

D O I：

10.1038/ng.735

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：117 / U57

页数：6

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