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

GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group ; Wellcome Trust Case Control Consortium 2 ; Kaixin Zhou ; Celine Bellenguez ; Chris CA Spencer ; Amanda J Bennett ; Ruth L Coleman ; Roger Tavendale ; Simon A Hawley ; Louise A Donnelly ; +43 more... 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 SF Doney ; Helen Colhoun ; Andrew D Morris ; Calum Sutherland ; D Grahame Hardie ; Leena Peltonen ; Mark I McCarthy ; Rury R Holman ; Colin NA Palmer ; Peter Donnelly ; Ewan R Pearson ; (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature genetics, 43 (2). pp. 117-120. ISSN 1061-4036 DOI: 10.1038/ng.735
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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.
Item Type Article
Keywords ACTIVATED PROTEIN-KINASE, GENOME-WIDE ASSOCIATION, ATAXIA-TELANGIECTASIA, CANCER, CELLS, RISK, AMPK, IDENTIFICATION, HOMEOSTASIS, REDUCTASE
ISI 286623800008
Date Deposited 17 Oct 2011 13:23

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