1976 Fig. 1a, electronic supplementary material [ESM] Fig. 1). When the analysis was restricted to those with a baseline HbA1c >7.0 % (53 mmol/mol), similar results were obtained (ESM Table 1). In the meta-analysis of the three novel cohorts where HbA1c reduction was assessed as a quantita- tive trait, there was no significant effect of rs11212617 on HbA1c reduction, partly because of the CARDS data being in the opposite direction to the other two cohorts, as reported previously (Fig. 1b). In the combined meta-analysis of all five replication cohorts from this and our previous study, the C allele was associated with an HbA1c decrease of −0.050 (95 % CI −0.089, −0.010) per copy of the C allele (p 0 0.013; I2 0 59%, p 0 0.05; pEgger 0 0.44; Table 3, Fig. 1b, ESM Fig. 1b). Again, when the analysis was restricted to those –0.3 –0.2 –0.1 0 0.1 0.2 0.3 Fig. 1 Association between rs11212617, metformin treatment re- sponse and treatment HbA1c in different cohorts. The grey squares and horizontal lines indicate (a) the cohort-specific ORs and 95% CI for the ability to reach the treatment target of HbA1c ≤7% (53 mmol/ mol) and (b) the cohort-specific β-coefficients and 95% CI for the treatment HbA1c as a continuous variable. The size of the squares is proportional to the weights of the studies. GoDARTS and UKPDS data were from Zhou et al [8] a This study DCS (this study) Rotterdam (this study) CARDS (this study) Subtotal Previously published GoDARTS, Zhou et al (2011) [8] UKPDS, Zhou et al (2011) [8] Subtotal Overall b This study DCS (this study) Rotterdam (this study) CARDS (this study) Subtotal Previously published GoDARTS, Zhou et al (2011) [8] UKPDS, Zhou et al (2011) [8] Subtotal Overall 0.5 1.0 1.5 2.0 Diabetologia (2012) 55:1971–1977 with a baseline HbA1c above 7.0 % (53 mmol/mol), similar results were obtained (ESM Table 2). Discussion In this study, we show replication of the reported association between a SNP at a locus that includes the ATM gene and glycaemic treatment success with metformin in the Dutch DCS cohort [8]. We noted a similar, although non-significant, trend in the smaller Rotterdam Study, but this trend was not observed in another small study, CARDS. Meta-analysis of data from these cohorts, which, despite intrinsic differences, provide clear, directionally consistent effects and shows replication of the previously reported association [8]. Importantly the effect of the SNP on metformin treatment success was observed in most cohorts, while there was no evidence for bias, and the characteristics of the cohorts differ, including data from population-based cohorts, pro- spective cohorts and clinical trials, indicating that the effect and its size are robust across European white populations. Furthermore, it is important to note that the association with treatment success is present regardless of baseline HbA1c, providing further evidence for the robustness of this observation. The effect in the monotherapy group is larger than in the dual therapy group, as observed in the previous study. The underlying mechanism of this observation is unknown. As metformin is the recommended first-line therapy, patients receiving metformin monotherapy are probably earlier in their disease process. Accordingly, the observed difference between mono and dual therapy might be explained by the negative effects of prolonged disease duration on treatment efficacy. However, it might also be that sulfonylurea therapy antagonises some of metformin’s effects mediated through mTOR-dependent and -independent signalling, as has been suggested recently by Wang et al [16]. Further research is required to elucidate the exact underlying mechanism. The effect of the SNP on the ability to achieve HbA1c ≤7 % (53 mmol/mol) is stronger than the quantitative HbA1c reduction, yet the quantitative trait should have greater statistical power. One possible explanation for the ‘treat-to- target’ model appearing to be better is that the patients and clinicians aiming for a particular target may not intensify treatment further once it is achieved. The low baseline HbA1c of 6.7 % (50 mmol/mol) in the DCS probably reflects increased awareness of diabetes among patients and care- givers and current prescribing practice, where metformin is introduced immediately after diagnosis and based on fasting glucose rather than HbA1c [17]. This most likely explains the lack of a genotype effect on HbA1c reduction in this cohort, as there is not much scope for the absolute HbA1c to decrease on metformin initiation.