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

Zhou, K., Bellenguez, C., Spencer, C. C. A., Bennett, A. J., Coleman, R. L., Tavendale, R., Hawley, S. A., Donnelly, L. A., Schofield, C., Groves, C. J., Burch, L., Carr, F., Strange, A., Freeman, C., Blackwell, J. M., Bramon, E., Brown, M. A., Casas, J. P., Corvin, A., Craddock, N., Deloukas, P., Dronov, S., Duncanson, A., Edkins, S., Gray, E., Hunt, S., Jankowski, J., Langford, C., Markus, H. S., Mathew, C. G., Plomin, R., Rautanen, A., Sawcer, S. J., Samani, N. J., Trembath, R., Viswanathan, A. C., Wood, N. W., Harries, L. W., Hattersley, A. T., Doney, A. S. F., Colhoun, H., Morris, A. D., Sutherland, C., Hardie, D. G., Peltonen, L., McCarthy, M. I., Holman, R. R., Palmer, C. N. A., Donnelly, P., & Pearson, E. R. (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature Genetics, 43(2), pp. 117-120.

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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 P×-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. © 2011 Nature America, Inc. All rights reserved.

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ID Code: 89353
Item Type: Journal Article
Refereed: Yes
Additional Information: Cited By :157
Export Date: 21 September 2015
CODEN: NGENE
Correspondence Address: Pearson, E. R.; Biomedical Research Institute, University of Dundee, Dundee, United Kingdom; email: e.pearson@cpse.dundee.ac.uk
Keywords: 2 morpholino 6 (1 thianthrenyl) 4 pyranone, ATM protein, hydroxymethylglutaryl coenzyme A reductase kinase, metformin, animal cell, cancer cell culture, drug mechanism, genetic association, human, major clinical study, non insulin dependent diabetes mellitus, nonhuman, priority journal, protein phosphorylation, rat, review, single nucleotide polymorphism, treatment outcome, Animals, Carcinoma, Hepatocellular, Cell Cycle Proteins, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Dose-Response Relationship, Drug, Genome-Wide Association Study, Humans, Hypoglycemic Agents, Liver Neoplasms, Polymorphism, Single Nucleotide, Protein Kinases, Protein-Serine-Threonine Kinases, Rats, Scotland, Tumor Suppressor Proteins, Ataxia telangiectasia, Rattus
DOI: 10.1038/ng.735
ISSN: 1061-4036
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright Nature America Inc
Deposited On: 21 Oct 2015 02:25
Last Modified: 19 Aug 2016 03:22

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