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 Betteridge, S 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

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. 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. 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.