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

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We carried out a GWA study on glycaemic response to metformin in 1024 Scottish patients with type 2 diabetes. Replication was in two cohorts consisting of 1783 Scottish patients and 1113 patients from the UK Prospective...

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Detalles Bibliográficos
Autores principales: Zhou, Kaixin, Bellenguez, Celine, Spencer, Chris CA, 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, Harries, Lorna W, Hattersley, Andrew T, Doney, Alex SF, 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
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030919/
https://www.ncbi.nlm.nih.gov/pubmed/21186350
http://dx.doi.org/10.1038/ng.735
Descripción
Sumario:Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We carried out a GWA study on glycaemic response to metformin in 1024 Scottish patients with type 2 diabetes. Replication was in two cohorts consisting of 1783 Scottish patients and 1113 patients from the UK Prospective Diabetes Study. In a meta-analysis (n=3920) we observed an association (P=2.9 *10(−9)) for a SNP rs11212617 at a locus containing the ataxia telangiectasia mutated (ATM) gene with an odds ratio of 1.35 (95% CI 1.22 to 1.49) for treatment success. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMPK 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 AMPK, and variation in this gene alters glycaemic response to metformin.

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