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