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; Qi Ping 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, Qi Ping 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Interindividual 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 statintreated individuals, providing a total sample size of 27 720 individuals. The only associations of genomewide 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 (US)
Pages (from-to)	835-845
Number of pages	11
Journal	Journal of medical genetics
Volume	53
Issue number	12
DOIs	https://doi.org/10.1136/jmedgenet-2016-103966
State	Published - Dec 1 2016

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1136/jmedgenet-2016-103966

Cite this

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. P., 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

Postmus, I, Warren, HR, Trompet, S, Arsenault, BJ, Avery, CL, Bis, JC, Chasman, DI, de Keyser, CE, Deshmukh, HA, Evans, DS, Feng, QP, 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, YDI, 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, CT, 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, WQ, 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, JC, 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

@article{df85beca29c64e76bfe00d6dc6fee56a,

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. Interindividual 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 statintreated individuals, providing a total sample size of 27 720 individuals. The only associations of genomewide 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.",

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 Feng, {Qi Ping} 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 Liu, {Ching Ti} 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, {Wei Qi} 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 Tardif, {Jean Claude} and Caulfield, {Mark J.} and Jukema, {J. Wouter} and Rotter, {Jerome I.} and Krauss, {Ronald M.}",

note = "Funding Information: PROSPER/PHASE: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was supported by an investigator initiated grant from Bristol-Myers Squibb, USA. The study was conducted, analysed and reported independently of the company. The GWAS project PHASE has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004. A part of the genotyping was funded by The Netherlands Consortium for Healthy Ageing (NGI: 05060810). Professor Dr J W Jukema is an established clinical investigator of The Netherlands Heart Foundation (2001 D 032). ASCOT: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial was funded by an investigator initiated grant from Pfizer USA. The study was investigator-led and was conducted, analysed and reported independently of the company. The Genome-wide Association Scan was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity and the Medical Research Council through G952010. CARDS: The authors thank the other investigators, the staff and the participants of the CARDS study. A full list of CARDS investigators can be found in original CARDS paper.38 CARDS was funded by grants to the Universities of London and Manchester by Pfizer, Diabetes UK and the Department of Health. PARC: This research was supported by the National Institutes of Health: grant U19 HL069757 from the National Heart, Lung, and Blood Institute; and grant UL1TR000124 from the National Center for Advancing Translational Sciences. TNT: The TNT study was funded by Pfizer, who also provided support for genotyping. AGES: This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. BioVU: BioVU receives support through the National Center for Research Resources UL1 RR024975, which is now the National Center for Advancing Translational Sciences, 2 UL1 TR000445. Genotyping was supported via grant U01-HG04603 from the National Human Genome Research Institute and RC2-GM092318 from the National Institute of General Medical Sciences. CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data were supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham HS: The Framingham Heart Study work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (contract no. N01-HC-25195), its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278) and based upon analyses by Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Also supported by R01HL103612 (PI Psaty, subcontract PI, Vasan). Health ABC: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HVH: This Heart and Vascular Health Study research was supported by NHLBI grants HL085251, HL073410, HL085251 and HL068986. MESA: The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Additional funding was supported in part by the Clinical Translational Science Institute grant UL1RR033176 and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124. The authors thank the other investigators in the Pharmarcogenetics Working Group, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www. mesa-nhlbi.org. Rotterdam Study: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission and Municipality of Rotterdam. This work was supported by the Netherlands Genomics Initiative (NGI) Netherlands Organization for Scientific Research (NOW; 050-060-810). JUPITER: Genetic analysis in JUPITER was supported by a research grant from AstraZeneca to DC and PM. GoDARTS: We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Wellcome Trust provides support for Wellcome Trust UK Type 2 Diabetes Case Control Collection (GoDARTS) and informatics support is provided by the Chief Scientist Office. The Wellcome Trust funds the Scottish Health Informatics Programme, provides core support for the Wellcome Trust Centre for Human Genetics in Oxford and funds the Wellcome Trust Case Control Consortium 2. This research was specifically funded by Diabetes UK (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,

day = "1",

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

language = "English (US)",

volume = "53",

pages = "835--845",

journal = "Journal of medical genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "12",

}

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, Qi Ping

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 - Funding Information: PROSPER/PHASE: The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was supported by an investigator initiated grant from Bristol-Myers Squibb, USA. The study was conducted, analysed and reported independently of the company. The GWAS project PHASE has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement HEALTH-F2-2009-223004. A part of the genotyping was funded by The Netherlands Consortium for Healthy Ageing (NGI: 05060810). Professor Dr J W Jukema is an established clinical investigator of The Netherlands Heart Foundation (2001 D 032). ASCOT: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) trial was funded by an investigator initiated grant from Pfizer USA. The study was investigator-led and was conducted, analysed and reported independently of the company. The Genome-wide Association Scan was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity and the Medical Research Council through G952010. CARDS: The authors thank the other investigators, the staff and the participants of the CARDS study. A full list of CARDS investigators can be found in original CARDS paper.38 CARDS was funded by grants to the Universities of London and Manchester by Pfizer, Diabetes UK and the Department of Health. PARC: This research was supported by the National Institutes of Health: grant U19 HL069757 from the National Heart, Lung, and Blood Institute; and grant UL1TR000124 from the National Center for Advancing Translational Sciences. TNT: The TNT study was funded by Pfizer, who also provided support for genotyping. AGES: This study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. BioVU: BioVU receives support through the National Center for Research Resources UL1 RR024975, which is now the National Center for Advancing Translational Sciences, 2 UL1 TR000445. Genotyping was supported via grant U01-HG04603 from the National Human Genome Research Institute and RC2-GM092318 from the National Institute of General Medical Sciences. CHS: This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data were supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham HS: The Framingham Heart Study work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (contract no. N01-HC-25195), its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278) and based upon analyses by Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Also supported by R01HL103612 (PI Psaty, subcontract PI, Vasan). Health ABC: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. HVH: This Heart and Vascular Health Study research was supported by NHLBI grants HL085251, HL073410, HL085251 and HL068986. MESA: The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and RR-024156. Additional funding was supported in part by the Clinical Translational Science Institute grant UL1RR033176 and is now at the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124. The authors thank the other investigators in the Pharmarcogenetics Working Group, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www. mesa-nhlbi.org. Rotterdam Study: The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission and Municipality of Rotterdam. This work was supported by the Netherlands Genomics Initiative (NGI) Netherlands Organization for Scientific Research (NOW; 050-060-810). JUPITER: Genetic analysis in JUPITER was supported by a research grant from AstraZeneca to DC and PM. GoDARTS: We are grateful to all the participants who took part in this study, to the general practitioners, to the Scottish School of Primary Care for their help in recruiting the participants, and to the whole team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Wellcome Trust provides support for Wellcome Trust UK Type 2 Diabetes Case Control Collection (GoDARTS) and informatics support is provided by the Chief Scientist Office. The Wellcome Trust funds the Scottish Health Informatics Programme, provides core support for the Wellcome Trust Centre for Human Genetics in Oxford and funds the Wellcome Trust Case Control Consortium 2. This research was specifically funded by Diabetes UK (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 - 2016/12/1

Y1 - 2016/12/1

N2 - Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Interindividual 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 statintreated individuals, providing a total sample size of 27 720 individuals. The only associations of genomewide 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. Interindividual 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 statintreated individuals, providing a total sample size of 27 720 individuals. The only associations of genomewide 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.

UR - http://www.scopus.com/inward/record.url?scp=84984996454&partnerID=8YFLogxK

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U2 - 10.1136/jmedgenet-2016-103966

DO - 10.1136/jmedgenet-2016-103966

M3 - Article

C2 - 27587472

AN - SCOPUS:84984996454

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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