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

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 John ORCID: https://orcid.org/0000-0003-2171-0610, 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 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 and Pearson, Ewan R. 2010. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature Genetics 43 (2) , pp. 117-120. 10.1038/ng.735

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	1061-4036
Last Modified:	20 Oct 2022 08:58
URI:	https://orca.cardiff.ac.uk/id/eprint/30224

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