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Cited by 225Lipoproteins and Cardiovascular HealthGenetic Associations and EpidemiologyPharmacogenetics and Drug Metabolism

The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.

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

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Mangravite, Lara M., Engelhardt, Barbara E., Medina, Marisa W., Smith, Joshua D., Brown, Christopher D., Chasman, Daniel I., Mecham, Brigham H., Howie, Bryan, Shim, Heejung, Naidoo, Devesh, 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.·2013·Nature
DOI 10.1038/nature12508PMC PMC3933266
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Abstract

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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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
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-08-28
Volume
502
Issue
7471
Pages
377-380
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature12508
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
Licence
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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