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


Zhou, KX; Bellenguez, C; Spencer, CCA; Bennett, AJ; Coleman, RL; Tavendale, R; Hawley, SA; Donnelly, LA; Schofield, C; Groves, CJ; Burch, L; Carr, F; Strange, A; Freeman, C; Blackwell, JM; Bramon, E; Brown, MA; Casas, JP; Corvin, A; Craddock, N; Deloukas, P; Dronov, S; Duncanson, A; Edkins, S; Gray, E; Hunt, S; Jankowski, J; Langford, C; Markus, HS; Mathew, CG; Plomin, R; Rautanen, A; Sawcer, SJ; Samani, NJ; Trembath, R; Viswanathan, AC; Wood, NW; Harries, LW; Hattersley, AT; Doney, ASF; Colhoun, H; Morris, AD; Sutherland, C; Hardie, DG; Peltonen, L; McCarthy, MI; Holman, RR; Palmer, CNA; Donnelly, P; Pearson, ER; (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nature genetics, 43 (2). 117-U57. ISSN 1061-4036 DOI: https://doi.org/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 x 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
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
Research Centre: Centre for Global Non-Communicable Diseases (NCDs)
PubMed ID: 21186350
Web of Science ID: 286623800008
URI: http://researchonline.lshtm.ac.uk/id/eprint/1304

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