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A statin-dependent QTL for GATM expression is associated with statin-induced myopathy
Open accessAbstract
Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, 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 treatment. 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.
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“Two independent studies showed that genotypes associated with statin-induced down-regulation of expression of the gene encoding GATM were associated with protection from statin-induced myopathy.116”
From Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management (2015) · cites this paper as [116]
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Metadata
- Authors
- Mangravite, L. M., Engelhardt, B. E., Medina, M. W., Smith, J. D., Brown, C. D., Chasman, D. I., Mecham, B. H., Howie, B., Shim, H., Naidoo, D., Feng, Q., Rieder, M. J., Chen, Y.-D. I., Rotter, J. I., Ridker, P. M., Hopewell, J. C., Parish, S., Armitage, J., Collins, R., Wilke, R. A., Nickerson, D. A., Stephens, M., & Krauss, R. M.
- Affiliations
- Sage Bionetworks (US)
- Duke University (US)
- University of Washington (US)
- University of Pennsylvania (US)
- Brigham and Women's Hospital (US)
- University of Chicago (US)
- Vanderbilt University Medical Center (US)
- The Lundquist Institute (US)
- University of Oxford (GB)
- Corresponding author
- Mangravite, Lara M.
- Stephens, Matthew
- Krauss, Ronald M.
- ORCID
- Mangravite, Lara M.
- Engelhardt, Barbara E.
- Medina, Marisa W.
- Smith, Joshua D.
- Chasman, Daniel I.
- Shim, Heejung
- Feng, QiPing
- Rieder, Mark J.
- Chen, Yii.-Der I.
- Rotter, Jerome I.
- Ridker, Paul M.
- Hopewell, Jemma C.
- Parish, Sarah
- Armitage, Jane
- Collins, Rory
- Wilke, Russell A.
- Nickerson, Deborah A.
- Stephens, Matthew
- Krauss, Ronald M.
- Venue
- Nature
- Published
- 2013-08-28
- Volume
- 502
- Issue
- 7471
- Pages
- 377-380
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3933266
- OpenAlex
- W1985629708
- Cited by
- 224
- References
- 41
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 11 · 2023: 14 · 2022: 12 · 2021: 13 · 2020: 12 · 2019: 19 · 2018: 19 · 2017: 15 · 2016: 22 · 2015: 25 · 2014: 42 · 2013: 8
- FWCI
- 31.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- British Heart Foundation
- National Institutes of Health (UL1TR000124)
- National Heart, Lung, and Blood Institute (R01HL104133, U01HL069757, U01-HL69757)
- National Human Genome Research Institute (R00HG006265, K99/R00HG006265, R56HG002585, HG002585, K99HG006265, R01HG002585)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- statin-induced myopathy, GATM, creatine synthesis, expression quantitative trait loci, simvastatin, gene expression regulation, statin toxicity, hepatocyte gene expression, drug-gene interactions, lymphoblastoid cell lines
- MeSH terms
- Amidinotransferases, Cell Line, Cholesterol, Gene Expression Regulation, Humans, Lymphocytes, Muscular Diseases, Transcription, Genetic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sterol Regulatory Element Binding Proteins, Gene Knockdown Techniques
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