Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes.
GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group None., Wellcome Trust Case Control Consortium 2 None., Zhou K., Bellenguez C., Spencer CC., 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., MAGIC investigators None., Harries LW., Hattersley AT., Doney AS., Colhoun H., Morris AD., Sutherland C., Hardie DG., Peltonen L., McCarthy MI., Holman RR., Palmer CN., Donnelly P., Pearson ER.
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.