Publication Date:
2013-09-03
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933266/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- HG002585/HG/NHGRI NIH HHS/ -- K99/R00HG006265/HG/NHGRI NIH HHS/ -- MC_U137686853/Medical Research Council/United Kingdom -- P30 DK063491/DK/NIDDK NIH HHS/ -- R00 HG006265/HG/NHGRI NIH HHS/ -- R01 HG002585/HG/NHGRI NIH HHS/ -- R01 HL104133/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL69757/HL/NHLBI NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Oct 17;502(7471):377-80. doi: 10.1038/nature12508. Epub 2013 Aug 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sage Bionetworks, 1100 Fairview Avenue North, Seattle, Washington 98109, USA. lara.mangravite@sagebase.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995691" target="_blank"〉PubMed〈/a〉
Keywords:
Amidinotransferases/deficiency/*genetics/metabolism
;
Cell Line
;
Cholesterol/deficiency/metabolism/pharmacology
;
Gene Expression Regulation/*drug effects
;
Gene Knockdown Techniques
;
Humans
;
Hydroxymethylglutaryl-CoA Reductase Inhibitors/*adverse effects/pharmacology
;
Lymphocytes/cytology/drug effects/metabolism
;
Muscular Diseases/*chemically induced/genetics/metabolism
;
Polymorphism, Single Nucleotide/genetics
;
Quantitative Trait Loci/*genetics
;
Simvastatin/*adverse effects/pharmacology
;
Sterol Regulatory Element Binding Proteins/metabolism
;
Transcription, Genetic/drug effects
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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