1974 the Illumina 550 k SNP array according to the manufac- turer’s instructions. Quality controls were as described pre- viously [15]. The call rate was 99.9%, and there was no deviation from HWE (p0 0.75). CARDS CARDS is a multicentre, placebo-controlled, double-blind study that enrolled 2,838 white men and wom- en between 40 and 75 years of age and randomised them to receive 10 mg/day of atorvastatin or placebo [14]. Patients had type 2 diabetes as well as one other risk factor for coronary heart disease. CARDS was carried out in 132 centres in the UK and Ireland. Metformin response as de- fined above could be characterised in 254 patients, and their characteristics are shown in Table 1. DNA was genotyped at Perlegen Sciences (Mountain View, CA, USA) using a proprietary SNP set comprising 599164 SNPs. The call rate for rs11212617 was 99%, and there was no deviation from HWE (p 00.1). Statistical analysis Two different outcomes were used to measure the metformin treatment response: (1) the ability to reach the treatment target of HbA1c ≤7 % (53 mmol/mol), analysed with logistic regression; (2) the decrease in HbA1c achieved, analysed as a quantitative trait with linear regres- sion. In each cohort, the total group of metformin users was analysed, but also a separate analysis was performed on patients starting metformin monotherapy or those starting dual therapy (where metformin is added to stable sulfonyl- urea treatment). Furthermore, two separate analyses were performed, the first on the total patient group regardless of the baseline HbA1c, and the second using only individuals with a baseline HbA1c >7 % (53 mmol/mol). The definition of the endpoints and covariates was similar to the original publication [8]. The covariates that were included in both the logistic and linear regression analyses were: baseline HbA1c, time between baseline HbA1c and metformin start date, drug adherence, daily dose and creatinine clearance, if measured in the cohort. In all cohorts with genome-wide association study data available, principal component analy- sis was used to exclude participants of non-white origin. A priori power calculations using Quanto software (http:// hydra.usc.edu/gxe) based on the ORs obtained in our orig- inal publication (1.35 or 1.25 when only stage 2 replication data are included) showed that we had respectively 86% and 61% power in the DCS, 29% and 18% in the Rotterdam Study, and 39% and 24% in CARDS (α 00.05). Data were considered to be significant at p < 0.05. Meta-analysis The three cohorts described above were in- cluded in the meta-analyses of treatment success and treat- ment HbA1c. To assess the overall robustness of the association, a second set of meta-analyses was performed by also including the stage 2 replication cohorts previously Diabetologia (2012) 55:1971–1977 described by Zhou et al: GoDARTS (n 0 1,965) and UKPDS (n 01,113). To avoid an overestimation of the effect of the SNP, the initial GoDARTS discovery cohort, which showed a very strong and highly significant association with treat- ment success (OR 1.64; 95% CI 1.37, 1.99), was not in- cluded. The DPP Study was not included because of the substantial nature of the difference in the phenotype [11]. For meta-analysis, a fixed-effects model was used. The inconsistency index I2 was used to assess between-study heterogeneity. To assess bias, funnel plots were generated, and Egger and Harbord tests were performed for, respec- tively, the linear and the logistic model. The meta-analysis was performed using Comprehensive Meta-analysis soft- ware (Biostat, Englewood, NJ, USA) and Stata software version 11.2 (Stata, College Station, TX, USA). Results The minor allele and genotype frequencies of the SNP, rs11212617, were similar in the three new cohorts (p> 0.2) and consistent with those reported for the GoDARTS and UKPDS cohorts. The minor allele frequency was 0.44, and the genotype frequencies are shown in Table 1. In the DCS cohort, including both patients receiving monotherapy and patients receiving dual therapy, we ob- served, as in our original publication, an association be- tween the minor C allele of rs11212617 and treatment success on metformin (OR 1.27 [95% 1.03, 1.58], p 00.028; Table 2). In the Rotterdam Study, we observed a similar but non-significant trend (OR 1.45 [95% CI 0.87, 2.39], p0 0.15), but this was not seen in the CARDS cohort (OR 1.03 [95% CI 0.68, 1.57], p0 0.86). In all three cohorts, the effect of rs11212617 was larger in those receiving monotherapy compared with dual therapy (Table 2). In the analysis of on-treatment HbA1c as a quantitative trait, there was no significant effect on HbA1c in either the DCS or the Rotterdam Study cohort. The only significant association was observed in the dual therapy group of the CARDS cohort, where the C allele was associated with higher- treatment HbA1c (Table 3). There was no association be- tween rs11212617 genotype and baseline HbA1c in any of the cohorts (data not shown). In the meta-analysis of the three cohorts, there was an increase in the odds of treatment success with the presence of the C allele (OR 1.24, p 0 0.016), in the whole group and where restricted to those starting metformin monotherapy alone (OR 1.38, p 0 0.015). These results are consistent in size and direction with our previous publication, such that a combined meta-analysis including the GoDARTS and UKPDS stage 2 replication datasets from that publication resulted in a combined OR of 1.25 (95% CI 1.13, 1.38), p 0 7.8 × 10−6; I2 0 0.0%, p 00.74; pHarbord 00.505 (Table 2,