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PMID: 21186350 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 43 ·No. 2 ·2011-02-00 ·Pages 117-20

GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, Wellcome Trust Case Control Consortium 2, Zhou K, Bellenguez C, Spencer CC, 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, MAGIC investigators, Harries LW, Hattersley AT, Doney AS, Colhoun H, Morris AD, Sutherland C, Hardie DG, Peltonen L, McCarthy MI, Holman RR, Palmer CN, Donnelly P, Pearson ER

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.

MeSH Terms
Animals Ataxia Telangiectasia Mutated Proteins Carcinoma, Hepatocellular/genetics,metabolism Cell Cycle Proteins/genetics DNA-Binding Proteins/genetics Diabetes Mellitus, Type 2/drug therapy,genetics Dose-Response Relationship, Drug Genome-Wide Association Study Humans Hypoglycemic Agents/pharmacology Liver Neoplasms/genetics,metabolism Metformin/pharmacology Polymorphism, Single Nucleotide Protein Kinases/metabolism Protein Serine-Threonine Kinases/genetics Rats Scotland Tumor Suppressor Proteins/genetics
Chemicals
Cell Cycle Proteins DNA-Binding Proteins Hypoglycemic Agents Tumor Suppressor Proteins Metformin Protein Kinases ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases
Authors & Affiliations
53 authors, click to expand affiliations / ORCID
GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group
Biomedical Research Institute, University of Dundee, Dundee, UK.
Wellcome Trust Case Control Consortium 2
Zhou Kaixin
Bellenguez Celine
Spencer Chris C A
Bennett Amanda J
Coleman Ruth L
Tavendale Roger
Hawley Simon A
Donnelly Louise A
Schofield Chris
Groves Christopher J
Burch Lindsay
Carr Fiona
Strange Amy
Freeman Colin
Blackwell Jenefer M
Bramon Elvira
Brown Matthew A
Casas Juan P
Corvin Aiden
Craddock Nicholas
Deloukas Panos
Dronov Serge
Duncanson Audrey
Edkins Sarah
Gray Emma
Hunt Sarah
Jankowski Janusz
Langford Cordelia
Markus Hugh S
Mathew Christopher G
Plomin Robert
Rautanen Anna
Sawcer Stephen J
Samani Nilesh J
Trembath Richard
Viswanathan Ananth C
Wood Nicholas W
MAGIC investigators
Harries Lorna W
Hattersley Andrew T
Doney Alex S F
Colhoun Helen
Morris Andrew D
Sutherland Calum
Hardie D Grahame
Peltonen Leena
McCarthy Mark I
Holman Rury R
Palmer Colin N A
Donnelly Peter
Pearson Ewan R
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.735
Published
2011-02-00
Epub
2010-00-26
Pages
117-20
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3030919
Subset
IM
Grants
Wellcome Trust · 084726/Z/08/Z · United Kingdom
Wellcome Trust · 085475/B/08/Z · United Kingdom
Medical Research Council · G19/2 · United Kingdom
Medical Research Council · G0901310 · United Kingdom
Wellcome Trust · 084726 · United Kingdom
Wellcome Trust · 085475/Z/08/Z · United Kingdom
Medical Research Council · G0601261 · United Kingdom
Chief Scientist Office · United Kingdom
Department of Health · PDA/02/06/016 · United Kingdom
Corrections
CommentIn
PMID: 21505202
CommentIn
PMID: 21845381
CommentIn
PMID: 22456732
CommentIn
PMID: 22456733
CommentIn
PMID: 23438881
External Links
PubMed source DOI: 10.1038/ng.735 PMC Full Text View journal details
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