Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk1 and have been shown to have beneficial effects in a broad range of patients2,3. However, statins are associated with an increased risk, albeit small, of clinical myopathy4 and type 2 diabetes5. Despite evidence for substantial genetic influence on LDL concentrations6, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy7,8,9 or toxicity10, 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 in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment7. 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 link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gene Expression Omnibus
The gene expression data have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE36868 and in Synapse (https://www.synapse.org/) under accession number syn299510. Code and analytical output complementary to this analysis are also provided through Synapse (https://www.synapse.org/#!Synapse:syn299510). The genotype data have been deposited in the database for genotypes and phenotypes (dbGaP, http://www.ncbi.nlm.nih.gov/gap) under accession number phs000481. The full set of eQTLs identified in our study is available at http://eqtl.uchicago.edu.
This project was funded by a grant from the US National Institutes of Health (NIH), U01 HL69757. B.E.E. was funded through the Bioinformatics Research Development Fund, supported by K. and G. Gould and NIH grant K99/R00 HG006265. M.S. was funded by NIH grant HG002585. We acknowledge the efforts of T. Kitchner and R. Mareedu for case validation in the Marshfield cohort. SEARCH was supported by the Medical Research Council, British Heart Foundation, National Health Service Genetic Knowledge Park, Centre National de Génotypage and Merck. The Heart Protection Study was funded by grants from the Medical Research Council, British Heart Foundation, Roche Vitamins and Merck. J.C.H. acknowledges support from the BHF Centre of Research Excellence, Oxford, UK. Genetic analysis in JUPITER was funded by a grant from AstraZeneca to D.I.C. and P.M.R.
Stable cis-eQTLs identified in association with gene expression following simvastatin exposure (treated, T), control exposure (control, C), or averaged across both exposures (averaged, S). Top eQTL listed for each gene. Significance threshold set at log10BF=3.24.
Supplementary Table 3 Stable trans-eQTLs identified in association with gene expression following simvastatin exposure (treated, T), control exposure (control, C), or averaged across both exposures (averaged, S). Significance threshold set at log10BF=7.20.
Differential cis-eQTLs identified by univariate analysis to be in association with gene expression following simvastatin exposure (treated, T), control exposure (control, C), or averaged across both exposures (averaged, S). Top eQTL listed for each gene with log10BF>2.0. Significance threshold set at log10BF=4.9.
Differential trans-eQTLs identified by univariate analysis as associated with gene expression following simvastatin exposure (treated, T), control exposure (control, C), or averaged across both exposures (averaged, S). Top eQTL listed for each gene with log10BF>5.0. Significance threshold set at log10BF=7.20.