Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

Iris Postmus, Helen R. Warren, Stella Trompet, Benoit J. Arsenault, Christy L. Avery, Joshua C. Bis, Daniel I. Chasman, Catherine E. de Keyser, Harshal A. Deshmukh, Daniel S. Evans, QiPing Feng, Xiaohui Li, Roelof A. J. Smit, Albert V. Smith, Fangui Sun, Kent D. Taylor, Alice M. Arnold, Michael R. Barnes, Bryan J. Barratt, John BetteridgeS. Matthijs Boekholdt, Eric Boerwinkle, Brendan M. Buckley, Y.-D. Ida Chen, Anton J. M. de Craen, Steven R. Cummings, Joshua C. Denny, Marie Pierre Dubé, Paul N. Durrington, Gudny Eiriksdottir, Ian Ford, Xiuqing Guo, Tamara B. Harris, Susan R. Heckbert, Albert Hofman, G. Kees Hovingh, John J. P. Kastelein, Leonore J. Launer, Ching-Ti Liu, Yongmei Liu, Thomas Lumley, Paul M. McKeigue, Patricia B. Munroe, Andrew Neil, Deborah A. Nickerson, Fredrik Nyberg, Eoin O'Brien, Christopher J. O'Donnell, Wendy Post, Neil Poulter, Ramachandran S. Vasan, Kenneth Rice, Stephen S. Rich, Fernando Rivadeneira, Naveed Sattar, Peter Sever, Sue Shaw-Hawkins, Denis C. Shields, P. Eline Slagboom, Nicholas L. Smith, Joshua D. Smith, Nona Sotoodehnia, Alice Stanton, David J. Stott, Bruno H. Stricker, Til Stürmer, André G. Uitterlinden, Wei-Qi Wei, Rudi G. J. Westendorp, Eric A. Whitsel, Kerri L. Wiggins, Russell A. Wilke, Christie M. Ballantyne, Helen M. Colhoun, L. Adrienne Cupples, Oscar H. Franco, Vilmundur Gudnason, Graham Hitman, Colin N. A. Palmer, Bruce M. Psaty, Paul M. Ridker, Jeanette M. Stafford, Charles M. Stein, Jean-Claude Tardif, Mark J. Caulfield, J. Wouter Jukema, Jerome I. Rotter, Ronald M. Krauss

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Abstract

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

Original languageEnglish
Pages (from-to)835-845
Number of pages11
JournalJournal of Medical Genetics
Volume53
Issue number12
Early online date1 Sep 2016
DOIs
Publication statusPublished - Dec 2016

Keywords

  • Pharmacogenetics
  • HDL-Cholesterol
  • Statins
  • Genome-wide association study

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    Postmus, I., Warren, H. R., Trompet, S., Arsenault, B. J., Avery, C. L., Bis, J. C., Chasman, D. I., de Keyser, C. E., Deshmukh, H. A., Evans, D. S., Feng, Q., Li, X., Smit, R. A. J., Smith, A. V., Sun, F., Taylor, K. D., Arnold, A. M., Barnes, M. R., Barratt, B. J., ... Krauss, R. M. (2016). Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. Journal of Medical Genetics, 53(12), 835-845. https://doi.org/10.1136/jmedgenet-2016-103966