A statin-dependent QTL for GATM expression is associated with statin-induced myopathy

Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk (1) and have been shown to have beneficial effects in a broad range of patients (2, 3). However, statins are associated with an increased risk, albeit small, of clinical myopathy (4) and type 2 diabetes (5). Despite evidence for substantial genetic influence on LDL concentrations (6), pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy (7-9) or toxicity (10), and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of invitrostatin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment (7). This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional linkbetween statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.
Analysis of individual variation in transcriptional response to drug treatment has successfully identified regulatory genetic variants that interact with treatment in model organisms (11) and human tissues (12-15). Cellular transcriptional [...]