1972 reach the treatment target of an HbA1c ≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. Results In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p0 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p 0 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously pub- lished cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p 00.016 and OR 1.25, 95% CI 1.33, 1.38, p 07.8 × 10−6, respectively). Conclusions/interpretation A gene variant near ATM is sig- nificantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response. Keywords Genetics of type 2 diabetes . Human . Meta-analysis . Metformin . Oral pharmacological agents Abbreviations AMPK AMP-activated protein kinase ATM Ataxia telangiectasia mutated P. Durrington University of Manchester, School of Medicine, Manchester, UK R. A. Calle Pfizer Ltd, New York, NY, USA A. Neil Department of Primary Health Care, University of Oxford, Oxford, UK G. Hitman Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK R. R. Holman : M. I. McCarthy Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK R. R. Holman : M. I. McCarthy Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK M. I. McCarthy Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK CARDS DCS DPP GoDARTS HWE LD SNP UKPDS Introduction Diabetologia (2012) 55:1971–1977 Collaborative Atorvastatin Diabetes Study Diabetes Care System West-Friesland Diabetes Prevention Program Genetics of Diabetes Audit and Research Tayside Hardy–Weinberg equilibrium Linkage disequilibrium Single-nucleotide polymorphism UK Prospective Diabetes Study Metformin is the first-choice treatment for type 2 diabetes [1]. It mainly improves fasting glucose levels by decreasing hepatic glucose production by inhibiting the mitochondrial respiratory-chain complex [2, 3], leading to activation of the AMP-activated protein kinase (AMPK) [4] through in- creased cellular AMP [5]. Activation of the AMPK path- ways was thought to be an important underlying mechanism involved in the inhibition of hepatic gluconeogenesis by metformin [6]; however, AMPK-independent glucose- lowering effects of metformin have been described recently [7], and therefore the exact molecular mechanism of action remains unclear. Our recent genome-wide association study revealed that the single-nucleotide polymorphism (SNP) rs11212617, lo- cated near the ataxia telangiectasia mutated (ATM) gene, is associated with metformin treatment response [8]. It has been shown in UK participants with type 2 diabetes mellitus from the GoDARTS (Genetics of Diabetes Audit and Re- search Tayside) and UKPDS (UK Prospective Diabetes Study) cohorts (n 03,920) that the minor C allele of rs11212617 is associated with two successful treatment out- comes: (1) the ability to achieve HbA1c values ≤7% (53 mmol/mol); (2) lower HbA1c when analysed as a quan- titative trait [8]. rs11212617 is located in a large linkage disequilibrium (LD) block that includes other genes as well; however, ATM is the most likely candidate to be involved [9, 10]. In the Diabetes Prevention Program (DPP, n 02,981), there was no evidence of an association between rs11212617 and the effect of metformin in delaying disease progression from impaired glucose tolerance to diabetes (CC vs AA, HR 1.22) [95% CI 0.86, 1.74] p 0 0.27) [11]. Lack of replication is often caused by the use of different phenotypes. As the progression to diabetes phenotype differs markedly from the type 2 diabetes mellitus phenotype, we have attempted to replicate our original finding in three independent cohorts using the identical phenotypic definition to that used in the original discovery. For this study, we used the Diabetes Care System West-Friesland (DCS) [12]