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 × 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.
authors.affiliation: Biomedical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhou
authors.forename: Celine
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authors.lastname: Bellenguez
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authors.initials: CC
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authors.forename: Amanda J
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authors.forename: Elvira
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authors.lastname: Bramon
authors.forename: Matthew A
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authors.lastname: Brown
authors.forename: Juan P
authors.initials: JP
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authors.lastname: Corvin
authors.forename: Nicholas
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authors.lastname: Craddock
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
authors.forename: Serge
authors.initials: S
authors.lastname: Dronov
authors.forename: Audrey
authors.initials: A
authors.lastname: Duncanson
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Emma
authors.initials: E
authors.lastname: Gray
authors.forename: Sarah
authors.initials: S
authors.lastname: Hunt
authors.forename: Janusz
authors.initials: J
authors.lastname: Jankowski
authors.forename: Cordelia
authors.initials: C
authors.lastname: Langford
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Markus
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mathew
authors.forename: Robert
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authors.lastname: Plomin
authors.forename: Anna
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authors.lastname: Rautanen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawcer
authors.forename: Nilesh J
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authors.lastname: Samani
authors.forename: Richard
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authors.lastname: Trembath
authors.forename: Ananth C
authors.initials: AC
authors.lastname: Viswanathan
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Alex S F
authors.initials: AS
authors.lastname: Doney
authors.forename: Helen
authors.initials: H
authors.lastname: Colhoun
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Calum
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authors.lastname: Sutherland
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Rury R
authors.initials: RR
authors.lastname: Holman
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Pearson
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D055106:Genome-Wide Association Study; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051381:Rats; D012606:Scotland; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007004:Hypoglycemic Agents; D025521:Tumor Suppressor Proteins; D008687:Metformin; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases