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

被引：175

作者：

Mangravite, Lara M. ^{[1
]}

Engelhardt, Barbara E. ^{[2
]}

Medina, Marisa W. ^{[3
]}

Smith, Joshua D. ^{[4
]}

Brown, Christopher D. ^{[5
]}

Chasman, Daniel I. ^{[6
]}

Mecham, Brigham H. ^{[1
]}

Howie, Bryan ^{[2
]}

Shim, Heejung ^{[2
]}

Naidoo, Devesh ^{[3
]}

Feng, QiPing ^{[7
]}

Rieder, Mark J. ^{[4
]}

Chen, Yii-Der I. ^{[8
]}

Rotter, Jerome I. ^{[8
]}

Ridker, Paul M. ^{[6
]}

Hopewell, Jemma C. ^{[9
,10
]}

Parish, Sarah ^{[9
,10
]}

Armitage, Jane ^{[9
,10
]}

Collins, Rory ^{[9
,10
]}

Wilke, Russell A. ^{[7
]}

Nickerson, Deborah A. ^{[4
]}

Stephens, Matthew ^{[2
,11
]}

Krauss, Ronald M. ^{[3
]}

机构：

[1] Sage Bionetworks, Seattle, WA 98109 USA

[2] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[3] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA

[4] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[5] Univ Penn, Dept Genet, Philadelphia, PA 19103 USA

[6] Brigham & Womens Hosp, Div Preventat Med, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA

[7] Vanderbilt Univ, Med Ctr, Div Clin Pharmacol, Dept Med, Nashville, TN 37232 USA

[8] Harbor UCLA Med Ctr, Los Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90502 USA

[9] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 7LF, England

[10] Univ Oxford, Epidemiol Studies Unit, Oxford OX3 7LF, England

[11] Univ Chicago, Dept Stat, Chicago, IL 60637 USA

来源：

NATURE | 2013年 / 502卷 / 7471期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

LIPID-LOWERING RESPONSE; SIMVASTATIN THERAPY; GENE-EXPRESSION; CHOLESTEROL; TRANSFORMATION; DISCOVERY; RISK; LOCI;

D O I：

10.1038/nature12508

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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 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(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 link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.

引用

页码：377 / +

页数：6

共 40 条

[1]

Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins [J].