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

Lara M. Mangravite; Barbara Engelhardt Martin; Marisa W. Medina; Joshua D. Smith; Christopher D. Brown; Daniel I. Chasman; Brigham H. Mecham; Bryan Howie; Heejung Shim; Devesh Naidoo; Qiping Feng; Mark J. Rieder; Yii Der I. Chen; Jerome I. Rotter; Paul M. Ridker; Jemma C. Hopewell; Sarah Parish; Jane Armitage; Rory Collins; Russell A. Wilke; Deborah A. Nickerson; Matthew Stephens; Ronald M. Krauss

doi:10.1038/nature12508

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

Lara M. Mangravite, Barbara Engelhardt Martin, Marisa W. Medina, Joshua D. Smith, Christopher D. Brown, Daniel I. Chasman, Brigham H. Mecham, Bryan Howie, Heejung Shim, Devesh Naidoo, Qiping Feng, Mark J. Rieder, Yii Der I. Chen, Jerome I. Rotter, Paul M. Ridker, Jemma C. Hopewell, Sarah Parish, Jane Armitage, Rory Collins, Russell A. WilkeDeborah A. Nickerson, Matthew Stephens, Ronald M. Krauss

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173 Scopus citations

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.

Original language	English (US)
Pages (from-to)	377-380
Number of pages	4
Journal	Nature
Volume	502
Issue number	7471
DOIs	https://doi.org/10.1038/nature12508
State	Published - 2013

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Mangravite, L. M., Engelhardt Martin, B., 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., ... Krauss, R. M. (2013). A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature, 502(7471), 377-380. https://doi.org/10.1038/nature12508

@article{ce4b60cef20049c2b0e3b0df59794e26,

title = "A statin-dependent QTL for GATM expression is associated with statin-induced myopathy",

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.",

author = "Mangravite, {Lara M.} and {Engelhardt Martin}, Barbara and Medina, {Marisa W.} and Smith, {Joshua D.} and Brown, {Christopher D.} and Chasman, {Daniel I.} and Mecham, {Brigham H.} and Bryan Howie and Heejung Shim and Devesh Naidoo and Qiping Feng and Rieder, {Mark J.} and Chen, {Yii Der I.} and Rotter, {Jerome I.} and Ridker, {Paul M.} and Hopewell, {Jemma C.} and Sarah Parish and Jane Armitage and Rory Collins and Wilke, {Russell A.} and Nickerson, {Deborah A.} and Matthew Stephens and Krauss, {Ronald M.}",

note = "Funding Information: Acknowledgements This project was funded by a grantfrom 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 G{\'e}notypage 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.",

year = "2013",

doi = "10.1038/nature12508",

language = "English (US)",

volume = "502",

pages = "377--380",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7471",

}

Mangravite, LM, Engelhardt Martin, B, Medina, MW, Smith, JD, Brown, CD, Chasman, DI, Mecham, BH, Howie, B, Shim, H, Naidoo, D, Feng, Q, Rieder, MJ, Chen, YDI, Rotter, JI, Ridker, PM, Hopewell, JC, Parish, S, Armitage, J, Collins, R, Wilke, RA, Nickerson, DA, Stephens, M & Krauss, RM 2013, 'A statin-dependent QTL for GATM expression is associated with statin-induced myopathy', Nature, vol. 502, no. 7471, pp. 377-380. https://doi.org/10.1038/nature12508

TY - JOUR

T1 - A statin-dependent QTL for GATM expression is associated with statin-induced myopathy

AU - Mangravite, Lara M.

AU - Engelhardt Martin, Barbara

AU - Medina, Marisa W.

AU - Smith, Joshua D.

AU - Brown, Christopher D.

AU - Chasman, Daniel I.

AU - Mecham, Brigham H.

AU - Howie, Bryan

AU - Shim, Heejung

AU - Naidoo, Devesh

AU - Feng, Qiping

AU - Rieder, Mark J.

AU - Chen, Yii Der I.

AU - Rotter, Jerome I.

AU - Ridker, Paul M.

AU - Hopewell, Jemma C.

AU - Parish, Sarah

AU - Armitage, Jane

AU - Collins, Rory

AU - Wilke, Russell A.

AU - Nickerson, Deborah A.

AU - Stephens, Matthew

AU - Krauss, Ronald M.

N1 - Funding Information: Acknowledgements This project was funded by a grantfrom 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.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885864334&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885864334&partnerID=8YFLogxK

U2 - 10.1038/nature12508

DO - 10.1038/nature12508

M3 - Article

C2 - 23995691

AN - SCOPUS:84885864334

SN - 0028-0836

VL - 502

SP - 377

EP - 380

JO - Nature

JF - Nature

IS - 7471

ER -

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

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