Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes by The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, 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, The Wellcome Trust Case Control Consortium 2 in Nature genetics (2010). PubMed

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.

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