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

doi:10.1136/jmedgenet-2016-103966

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 (Lead / Corresponding author)

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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 language	English
Pages (from-to)	835-845
Number of pages	11
Journal	Journal of Medical Genetics
Volume	53
Issue number	12
Early online date	1 Sept 2016
DOIs	https://doi.org/10.1136/jmedgenet-2016-103966
Publication status	Published - Dec 2016

Keywords

Pharmacogenetics
HDL-Cholesterol
Statins
Genome-wide association study

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10.1136/jmedgenet-2016-103966

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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

@article{6422f39e03114132969dfbac1f88d80a,

title = "Meta-analysis of genome-wide association studies of HDL cholesterol response to statins",

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.",

keywords = "Pharmacogenetics, HDL-Cholesterol, Statins, Genome-wide association study",

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

note = "This research was specifically funded by Diabetes UK 8 Postmus I, et al. J Med Genet 2016;0:1–11. doi:10.1136/jmedgenet-2016-103966 Genome-wide studies (07/0003525) and the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z). Genotyping of the GoDARTS samples (sample 2) was also funded as part of the EU IMI-SUMMIT programme.",

year = "2016",

month = dec,

doi = "10.1136/jmedgenet-2016-103966",

language = "English",

volume = "53",

pages = "835--845",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "12",

}

Postmus, I, Warren, HR, Trompet, S, Arsenault, BJ, Avery, CL, Bis, JC, Chasman, DI, de Keyser, CE, Deshmukh, HA, Evans, DS, Feng, Q, Li, X, Smit, RAJ, Smith, AV, Sun, F, Taylor, KD, Arnold, AM, Barnes, MR, Barratt, BJ, Betteridge, J, Boekholdt, SM, Boerwinkle, E, Buckley, BM, Chen, Y-DI, de Craen, AJM, Cummings, SR, Denny, JC, Dubé, MP, Durrington, PN, Eiriksdottir, G, Ford, I, Guo, X, Harris, TB, Heckbert, SR, Hofman, A, Hovingh, GK, Kastelein, JJP, Launer, LJ, Liu, C-T, Liu, Y, Lumley, T, McKeigue, PM, Munroe, PB, Neil, A, Nickerson, DA, Nyberg, F, O'Brien, E, O'Donnell, CJ, Post, W, Poulter, N, Vasan, RS, Rice, K, Rich, SS, Rivadeneira, F, Sattar, N, Sever, P, Shaw-Hawkins, S, Shields, DC, Slagboom, PE, Smith, NL, Smith, JD, Sotoodehnia, N, Stanton, A, Stott, DJ, Stricker, BH, Stürmer, T, Uitterlinden, AG, Wei, W-Q, Westendorp, RGJ, Whitsel, EA, Wiggins, KL, Wilke, RA, Ballantyne, CM, Colhoun, HM, Cupples, LA, Franco, OH, Gudnason, V, Hitman, G, Palmer, CNA, Psaty, BM, Ridker, PM, Stafford, JM, Stein, CM, Tardif, J-C, Caulfield, MJ, Jukema, JW, Rotter, JI & Krauss, RM 2016, 'Meta-analysis of genome-wide association studies of HDL cholesterol response to statins', Journal of Medical Genetics, vol. 53, no. 12, pp. 835-845. https://doi.org/10.1136/jmedgenet-2016-103966

TY - JOUR

T1 - Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

AU - Postmus, Iris

AU - Warren, Helen R.

AU - Trompet, Stella

AU - Arsenault, Benoit J.

AU - Avery, Christy L.

AU - Bis, Joshua C.

AU - Chasman, Daniel I.

AU - de Keyser, Catherine E.

AU - Deshmukh, Harshal A.

AU - Evans, Daniel S.

AU - Feng, QiPing

AU - Li, Xiaohui

AU - Smit, Roelof A. J.

AU - Smith, Albert V.

AU - Sun, Fangui

AU - Taylor, Kent D.

AU - Arnold, Alice M.

AU - Barnes, Michael R.

AU - Barratt, Bryan J.

AU - Betteridge, John

AU - Boekholdt, S. Matthijs

AU - Boerwinkle, Eric

AU - Buckley, Brendan M.

AU - Chen, Y.-D. Ida

AU - de Craen, Anton J. M.

AU - Cummings, Steven R.

AU - Denny, Joshua C.

AU - Dubé, Marie Pierre

AU - Durrington, Paul N.

AU - Eiriksdottir, Gudny

AU - Ford, Ian

AU - Guo, Xiuqing

AU - Harris, Tamara B.

AU - Heckbert, Susan R.

AU - Hofman, Albert

AU - Hovingh, G. Kees

AU - Kastelein, John J. P.

AU - Launer, Leonore J.

AU - Liu, Ching-Ti

AU - Liu, Yongmei

AU - Lumley, Thomas

AU - McKeigue, Paul M.

AU - Munroe, Patricia B.

AU - Neil, Andrew

AU - Nickerson, Deborah A.

AU - Nyberg, Fredrik

AU - O'Brien, Eoin

AU - O'Donnell, Christopher J.

AU - Post, Wendy

AU - Poulter, Neil

AU - Vasan, Ramachandran S.

AU - Rice, Kenneth

AU - Rich, Stephen S.

AU - Rivadeneira, Fernando

AU - Sattar, Naveed

AU - Sever, Peter

AU - Shaw-Hawkins, Sue

AU - Shields, Denis C.

AU - Slagboom, P. Eline

AU - Smith, Nicholas L.

AU - Smith, Joshua D.

AU - Sotoodehnia, Nona

AU - Stanton, Alice

AU - Stott, David J.

AU - Stricker, Bruno H.

AU - Stürmer, Til

AU - Uitterlinden, André G.

AU - Wei, Wei-Qi

AU - Westendorp, Rudi G. J.

AU - Whitsel, Eric A.

AU - Wiggins, Kerri L.

AU - Wilke, Russell A.

AU - Ballantyne, Christie M.

AU - Colhoun, Helen M.

AU - Cupples, L. Adrienne

AU - Franco, Oscar H.

AU - Gudnason, Vilmundur

AU - Hitman, Graham

AU - Palmer, Colin N. A.

AU - Psaty, Bruce M.

AU - Ridker, Paul M.

AU - Stafford, Jeanette M.

AU - Stein, Charles M.

AU - Tardif, Jean-Claude

AU - Caulfield, Mark J.

AU - Jukema, J. Wouter

AU - Rotter, Jerome I.

AU - Krauss, Ronald M.

N1 - This research was specifically funded by Diabetes UK 8 Postmus I, et al. J Med Genet 2016;0:1–11. doi:10.1136/jmedgenet-2016-103966 Genome-wide studies (07/0003525) and the Wellcome Trust (084727/Z/08/Z, 085475/Z/08/Z, 085475/B/08/Z). Genotyping of the GoDARTS samples (sample 2) was also funded as part of the EU IMI-SUMMIT programme.

PY - 2016/12

Y1 - 2016/12

N2 - 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.

AB - 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.

KW - Pharmacogenetics

KW - HDL-Cholesterol

KW - Statins

KW - Genome-wide association study

U2 - 10.1136/jmedgenet-2016-103966

DO - 10.1136/jmedgenet-2016-103966

M3 - Article

C2 - 27587472

SN - 0022-2593

VL - 53

SP - 835

EP - 845

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 12

ER -

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

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