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

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 s...

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Bibliographic Details
Published in:Diabetologia 2012-07, Vol.55 (7), p.1971-1977
Main Authors: van Leeuwen, N., Nijpels, G., Becker, M. L., Deshmukh, H., Zhou, K., Stricker, B. H. C., Uitterlinden, A. G., Hofman, A., van ’t Riet, E., Palmer, C. N. A., Guigas, B., Slagboom, P. E., Durrington, P., Calle, R. A., Neil, A., Hitman, G., Livingstone, S. J., Colhoun, H., Holman, R. R., McCarthy, M. I., Dekker, J. M., ’t Hart, L. M., Pearson, E. R.
Format: Article
Language:English
Subjects:
Aged
Ataxia
Biological and medical sciences
Cohort Studies
Collaboration
Diabetes
Diabetes Mellitus, Type 2 - blood
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - genetics
Diabetes. Impaired glucose tolerance
DNA Replication - drug effects
DNA Replication - genetics
Dose-Response Relationship, Drug
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Epidemiology
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Female
Genome-Wide Association Study
Glucose
Glycated Hemoglobin A - metabolism
Hospitals
Human Physiology
Humans
Hypoglycemic Agents - pharmacology
Hypoglycemic Agents - therapeutic use
Internal Medicine
Kinases
Male
Medical sciences
Medicine
Medicine & Public Health
Meta-analysis
Metabolic Diseases
Metformin - pharmacology
Metformin - therapeutic use
Middle Aged
Netherlands
Polymorphism
Polymorphism, Single Nucleotide
Prevention programs
Prospective Studies
Success
Treatment Outcome
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Summary: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.
ISSN:0012-186X
1432-0428
DOI:10.1007/s00125-012-2537-x