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Common Variants Near ATM Are Associated With Glycemic Response to Metformin in Type 2 Diabetes
GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group, et al
Nat Genet. 2011;43:117-120, Epub 2010 Dec 26
Summary
Metformin is commonly used as a first-line therapy in the treatment of type 2 diabetes, but glycemic response to the drug is highly variable. The investigators of the GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group performed a genome-wide association study (GWAS) to identify potential genetic modifiers for metformin response.
The GWAS included data from 3 patient groups: an initial discovery group (n = 1024) and a replication group (n = 1783) of patients with type 2 diabetes from a large Scottish observational genetic cohort, as well as an independent group of patients prospectively treated with metformin in the United Kingdom Prospective Diabetes Study (UKPDS) cohort (n = 1113). Response was measured by the ability to reduce glycated hemoglobin (A1c) levels below 7% in the first 18 months of therapy.
Polymorphisms near the ataxia-telangiectasia mutated (ATM) gene were significantly associated with metformin response, with an odds ratio of 1.35. Effects on baseline A1c, fasting insulin, and insulin resistance were all ruled out as sources of this signal.
Viewpoint
The investigators successfully identified polymorphisms associated with metformin response. The association signal falls in a large block of highly correlated polymorphisms spanning approximately 7 genes, including ATM, and the signal was centered over ATM.
Metformin exerts its antidiabetic action by reducing hepatic glucose production and increasing skeletal muscle glucose uptake following activation of adenosine monophosphate-activated protein kinase (AMPK). The investigators introduced a selective inhibitor of ATM into a rat cell line and demonstrated a reduction in the activation of AMPK by metformin. This finding supported their hypothesis that ATM is a driver of metformin response. In addition, individuals with ataxia-telangiectasia, which is caused by ATM loss-of-function mutations, have an increased risk for diabetes further supporting the link between ATM and glucose metabolism.
Unfortunately, the findings of this study are not likely to be directly applicable to clinical practice. The odds ratio associated with the signal is modest, especially for a pharmacogenetic modifier, and explains only 2.5% of the variability in metformin response. Either further modifiers of response need to be unveiled so that combinatorial predictive models can be developed, or more specific functional variants in ATM need to be identified to facilitate translation of this finding into clinical practice. If such markers are validated, carrier testing for ATM mutations may ultimately be useful in predicting metformin response.
Although immediate clinical utility is lacking, this study reveals a novel mechanism mediating metformin response, and demonstrates that pharmacogenetic approaches may be useful in unraveling further metformin modifiers as well as potential drug targets for the treatment of type 2 diabetes.
Abstract
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