Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Iris Postmus, Stella Trompet, Harshal A Deshmukh, Michael R Barnes, Xiaohui Li, Helen R Warren, Daniel I Chasman, Kaixin Zhou, Benoit J Arsenault, Louise A Donnelly, Kerri L Wiggins, Christy L Avery, Paula Griffin, QiPing Feng, Kent D Taylor, Guo Li, Daniel S Evans, Albert V Smith, Catherine E de Keyser, Andrew D Johnson, Anton J M de Craen, David J Stott, Brendan M Buckley, Ian Ford, Rudi G J Westendorp, P Eline Slagboom, Naveed Sattar, Patricia B Munroe, Peter Sever, Neil Poulter, Alice Stanton, Denis C Shields, Eoin O'Brien, Sue Shaw-Hawkins, Y-D Ida Chen, Deborah A Nickerson, Joshua D Smith, Marie Pierre Dubé, S Matthijs Boekholdt, G Kees Hovingh, John J P Kastelein, Paul M McKeigue, John Betteridge, Andrew Neil, Paul N Durrington, Alex Doney, Fiona Carr, Andrew Morris, Mark I McCarthy, Leif Groop, Emma Ahlqvist, Welcome Trust Case Control Consortium, Joshua C Bis, Kenneth Rice, Nicholas L Smith, Thomas Lumley, Eric A Whitsel, Til Stürmer, Eric Boerwinkle, Julius S Ngwa, Christopher J O'Donnell, Ramachandran S Vasan, Wei-Qi Wei, Russell A Wilke, Ching-Ti Liu, Fangui Sun, Xiuqing Guo, Susan R Heckbert, Wendy Post, Nona Sotoodehnia, Alice M Arnold, Jeanette M Stafford, Jingzhong Ding, David M Herrington, Stephen B Kritchevsky, Gudny Eiriksdottir, Leonore J Launer, Tamara B Harris, Audrey Y Chu, Franco Giulianini, Jean G MacFadyen, Bryan J Barratt, Fredrik Nyberg, Bruno H Stricker, André G Uitterlinden, Albert Hofman, Fernando Rivadeneira, Valur Emilsson, Oscar H Franco, Paul M Ridker, Vilmundur Gudnason, Yongmei Liu, Joshua C Denny, Christie M Ballantyne, Jerome I Rotter, L Adrienne Cupples, Bruce M Psaty, Colin N A Palmer, Jean-Claude Tardif, Helen M Colhoun, Graham Hitman, Ronald M Krauss, J Wouter Jukema, Mark J Caulfield, Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Christopher G Mathew, Jenefer M Blackwell, Matthew A Brown, Aiden Corvin, Mark I McCarthy, Chris C A Spencer, Iris Postmus, Stella Trompet, Harshal A Deshmukh, Michael R Barnes, Xiaohui Li, Helen R Warren, Daniel I Chasman, Kaixin Zhou, Benoit J Arsenault, Louise A Donnelly, Kerri L Wiggins, Christy L Avery, Paula Griffin, QiPing Feng, Kent D Taylor, Guo Li, Daniel S Evans, Albert V Smith, Catherine E de Keyser, Andrew D Johnson, Anton J M de Craen, David J Stott, Brendan M Buckley, Ian Ford, Rudi G J Westendorp, P Eline Slagboom, Naveed Sattar, Patricia B Munroe, Peter Sever, Neil Poulter, Alice Stanton, Denis C Shields, Eoin O'Brien, Sue Shaw-Hawkins, Y-D Ida Chen, Deborah A Nickerson, Joshua D Smith, Marie Pierre Dubé, S Matthijs Boekholdt, G Kees Hovingh, John J P Kastelein, Paul M McKeigue, John Betteridge, Andrew Neil, Paul N Durrington, Alex Doney, Fiona Carr, Andrew Morris, Mark I McCarthy, Leif Groop, Emma Ahlqvist, Welcome Trust Case Control Consortium, Joshua C Bis, Kenneth Rice, Nicholas L Smith, Thomas Lumley, Eric A Whitsel, Til Stürmer, Eric Boerwinkle, Julius S Ngwa, Christopher J O'Donnell, Ramachandran S Vasan, Wei-Qi Wei, Russell A Wilke, Ching-Ti Liu, Fangui Sun, Xiuqing Guo, Susan R Heckbert, Wendy Post, Nona Sotoodehnia, Alice M Arnold, Jeanette M Stafford, Jingzhong Ding, David M Herrington, Stephen B Kritchevsky, Gudny Eiriksdottir, Leonore J Launer, Tamara B Harris, Audrey Y Chu, Franco Giulianini, Jean G MacFadyen, Bryan J Barratt, Fredrik Nyberg, Bruno H Stricker, André G Uitterlinden, Albert Hofman, Fernando Rivadeneira, Valur Emilsson, Oscar H Franco, Paul M Ridker, Vilmundur Gudnason, Yongmei Liu, Joshua C Denny, Christie M Ballantyne, Jerome I Rotter, L Adrienne Cupples, Bruce M Psaty, Colin N A Palmer, Jean-Claude Tardif, Helen M Colhoun, Graham Hitman, Ronald M Krauss, J Wouter Jukema, Mark J Caulfield, Peter Donnelly, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Chris C A Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Peter Donnelly, Cordelia Langford, Sarah E Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Ines Barroso, Panos Deloukas, Christopher G Mathew, Jenefer M Blackwell, Matthew A Brown, Aiden Corvin, Mark I McCarthy, Chris C A Spencer

Abstract

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Conflict of interest statement

B.M.P. serves on the Data and Safety Monitoring Board of a clinical trial funded by the device manufacturer (Zoll LifeCor). N.P. and A.S. received funding from Pfizer for the extended follow-up of the ASCOT UK participants. D.I.C. and P.M.R. received research support for independent genetic analysis in JUPITER from AstraZeneca. F.N. and B.J.B. have employment, stock and stock options in AstraZeneca, a for-profit company engaged in the discovery, development, manufacture and marketing of proprietary therapeutics such as rosuvastatin, but do not consider that this creates any conflict of interest with the subject-matter of this publication. R.M.K. serves on the Merck Global Atherosclerosis Advisory Board. The remaining authors declare no competing financial interests.

Figures

Figure 1. Results of the GWAS meta-analysis.
Figure 1. Results of the GWAS meta-analysis.
Manhattan plot presenting the −log10P values from the combined meta-analysis (n=40,914) on LDL-C response after statin treatment. P values were generated using linear regression analysis.
Figure 2. Regional association plots of the…
Figure 2. Regional association plots of the genome-wide significant associations with LDL-C response after statin treatment.
The plots show the genome-wide significant associated loci in the combined meta-analysis (n=40,914), the APOE locus (a), the LPA locus (b), the SORT1/CELSR2/PSRC1 locus (c) and the SLCO1B1 locus (d) (generated using LocusZoom ( http://genome.sph.umich.edu/wiki/LocusZoom)). The colour of the SNPs is based on the LD with the lead SNP (shown in purple). The RefSeq genes in the region are shown in the lower panel. P values were generated using linear regression analysis.

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