Limits...
A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

van Leeuwen N, Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BH, Uitterlinden AG, Hofman A, van 't Riet E, Palmer CN, Guigas B, Slagboom PE, Durrington P, Calle RA, Neil A, Hitman G, Livingstone SJ, Colhoun H, Holman RR, McCarthy MI, Dekker JM, 't Hart LM, Pearson ER - Diabetologia (2012)

Bottom Line: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations.A gene variant near ATM is significantly 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.

ABSTRACT

Aims/hypothesis: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations.

Methods: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 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, p = 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 = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively).

Conclusions/interpretation: A gene variant near ATM is significantly 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.

Show MeSH

Related in: MedlinePlus

Association between rs11212617, metformin treatment response 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]
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369131&req=5

Fig1: Association between rs11212617, metformin treatment response 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]

Mentions: 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 = 0.016), in the whole group and where restricted to those starting metformin monotherapy alone (OR 1.38, p = 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 = 7.8 × 10−6; I2 = 0.0%, p = 0.74; pHarbord = 0.505 (Table 2, 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 quantitative 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 = 0.013; I2 = 59%, p = 0.05; pEgger = 0.44; Table 3, Fig. 1b, ESM Fig. 1b). Again, when the analysis was restricted to those with a baseline HbA1c above 7.0 % (53 mmol/mol), similar results were obtained (ESM Table 2).Fig. 1


A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts.

van Leeuwen N, Nijpels G, Becker ML, Deshmukh H, Zhou K, Stricker BH, Uitterlinden AG, Hofman A, van 't Riet E, Palmer CN, Guigas B, Slagboom PE, Durrington P, Calle RA, Neil A, Hitman G, Livingstone SJ, Colhoun H, Holman RR, McCarthy MI, Dekker JM, 't Hart LM, Pearson ER - Diabetologia (2012)

Association between rs11212617, metformin treatment response 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]
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369131&req=5

Fig1: Association between rs11212617, metformin treatment response 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]
Mentions: 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 = 0.016), in the whole group and where restricted to those starting metformin monotherapy alone (OR 1.38, p = 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 = 7.8 × 10−6; I2 = 0.0%, p = 0.74; pHarbord = 0.505 (Table 2, 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 quantitative 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 = 0.013; I2 = 59%, p = 0.05; pEgger = 0.44; Table 3, Fig. 1b, ESM Fig. 1b). Again, when the analysis was restricted to those with a baseline HbA1c above 7.0 % (53 mmol/mol), similar results were obtained (ESM Table 2).Fig. 1

Bottom Line: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations.A gene variant near ATM is significantly 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.

ABSTRACT

Aims/hypothesis: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations.

Methods: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 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, p = 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 = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively).

Conclusions/interpretation: A gene variant near ATM is significantly 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.

Show MeSH
Related in: MedlinePlus