Editors' ChoiceGenomic Medicine

Drug-Induced Aches and Pains

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Science Translational Medicine  25 Sep 2013:
Vol. 5, Issue 204, pp. 204ec160
DOI: 10.1126/scitranslmed.3007631

Statins are commonly used medications to prevent cardiovascular disease. In general, statins are well tolerated. However, a small but clinically significant number of patients develop statin-induced muscular side effects such as aches, pains, or weakness (myopathy). The reasons why some patients develop statin-induced side effects have been difficult to identify. Certain genetic variants in drug transporters have been implicated; however, many people without these variants still get muscle aches. To look for genetic variation underlying how patients may respond to statins, Mangravite et al. used lymphoblastic cell lines (LCL) and discovered that a gene involved in muscle physiology may be to blame.

Mangravite et al. combined expression quantitative trait loci (eQTL) and differential gene expression analyses using LCLs derived from 480 patients and treated with simvastatin in vitro. The underlying assumption was that genetically determined variations in drug response can be revealed by differential changes in gene expression in LCLs with different genetic backgrounds. The authors identified six differential eQTLs. The top locus included a large group of variants near the GATM gene, and carriers of the minor allele had a decrease in GATM expression in response to simvastatin. Because GATM has a well-known role in muscle physiology, Mangravite et al. hypothesized that these same variants may underlie the risk for statin-induced myopathy. Using data from two previous cohorts of cases of statin-induced myopathy, the authors demonstrated that the same loci near GATM were protective for statin-induced myopathy in these patient cohorts. The mechanisms by which statin-induced reductions in GATM may alter the risk of statin-induced myopathy are not clear from this study. However, this work opens the possibility of using the differential eQTL approach in patient-derived cell lines as a general platform to understand the variability in drug responses, in turn providing better care for patients.

L. M. Mangravite et al., A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature, published online 28 August 2013 (10.1038/nature12508). [Full]

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