IDEAS home Printed from https://ideas.repec.org/a/plo/pone00/0218115.html
   My bibliography  Save this article

Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing

Author

Listed:
  • James S Floyd
  • Katarzyna M Bloch
  • Jennifer A Brody
  • Cyrielle Maroteau
  • Moneeza K Siddiqui
  • Richard Gregory
  • Daniel F Carr
  • Mariam Molokhia
  • Xiaoming Liu
  • Joshua C Bis
  • Ammar Ahmed
  • Xuan Liu
  • Pär Hallberg
  • Qun-Ying Yue
  • Patrik K E Magnusson
  • Diane Brisson
  • Kerri L Wiggins
  • Alanna C Morrison
  • Etienne Khoury
  • Paul McKeigue
  • Bruno H Stricker
  • Maryse Lapeyre-Mestre
  • Susan R Heckbert
  • Arlene M Gallagher
  • Hector Chinoy
  • Richard A Gibbs
  • Emmanuelle Bondon-Guitton
  • Russell Tracy
  • Eric Boerwinkle
  • Daniel Gaudet
  • Anita Conforti
  • Tjeerd van Staa
  • Colleen M Sitlani
  • Kenneth M Rice
  • Anke-Hilse Maitland-van der Zee
  • Mia Wadelius
  • Andrew P Morris
  • Munir Pirmohamed
  • Colin A N Palmer
  • Bruce M Psaty
  • Ana Alfirevic
  • on behalf of the PREDICTION-ADR Consortium and EUDRAGENE

Abstract

Aims: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM. Methods and results: SRM 3–5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3–5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance. Conclusions: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

Suggested Citation

  • James S Floyd & Katarzyna M Bloch & Jennifer A Brody & Cyrielle Maroteau & Moneeza K Siddiqui & Richard Gregory & Daniel F Carr & Mariam Molokhia & Xiaoming Liu & Joshua C Bis & Ammar Ahmed & Xuan Liu, 2019. "Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing," PLOS ONE, Public Library of Science, vol. 14(6), pages 1-13, June.
  • Handle: RePEc:plo:pone00:0218115
    DOI: 10.1371/journal.pone.0218115
    as

    Download full text from publisher

    File URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218115
    Download Restriction: no

    File URL: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0218115&type=printable
    Download Restriction: no

    File URL: https://libkey.io/10.1371/journal.pone.0218115?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Lara M. Mangravite & Barbara E. Engelhardt & Marisa W. Medina & Joshua D. Smith & Christopher D. Brown & Daniel I. Chasman & Brigham H. Mecham & Bryan Howie & Heejung Shim & Devesh Naidoo & QiPing Fen, 2013. "A statin-dependent QTL for GATM expression is associated with statin-induced myopathy," Nature, Nature, vol. 502(7471), pages 377-380, October.
    2. James S. Floyd & Joshua C. Bis & Jennifer A. Brody & Susan R. Heckbert & Kenneth Rice & Bruce M. Psaty, 2014. "GATM locus does not replicate in rhabdomyolysis study," Nature, Nature, vol. 513(7518), pages 1-3, September.
    3. D. F. Carr & A. Alfirevic & R. Johnson & H. Chinoy & T. van Staa & M. Pirmohamed, 2014. "GATM gene variants and statin myopathy risk," Nature, Nature, vol. 513(7518), pages 1-1, September.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Heejung Shim & Daniel I Chasman & Joshua D Smith & Samia Mora & Paul M Ridker & Deborah A Nickerson & Ronald M Krauss & Matthew Stephens, 2015. "A Multivariate Genome-Wide Association Analysis of 10 LDL Subfractions, and Their Response to Statin Treatment, in 1868 Caucasians," PLOS ONE, Public Library of Science, vol. 10(4), pages 1-20, April.
    2. Justyna A. Resztak & Jane Choe & Shreya Nirmalan & Julong Wei & Julian Bruinsma & Russell Houpt & Adnan Alazizi & Henriette E. Mair-Meijers & Xiaoquan Wen & Richard B. Slatcher & Samuele Zilioli & Rog, 2023. "Analysis of transcriptional changes in the immune system associated with pubertal development in a longitudinal cohort of children with asthma," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:plo:pone00:0218115. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: plosone (email available below). General contact details of provider: https://journals.plos.org/plosone/ .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.