The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction

Stella Trompet; Iris Postmus; on behalf of the GIST consortium and the CHARGE pharmacogenetics working group; Helen R. Warren; Raymond Noordam; Roelof A.J. Smit; Elizabeth Theusch; Xiaohui Li; Benoit Arsenault; Daniel I. Chasman; Graham A. Hitman; Patricia B. Munroe; Jerome I. Rotter; Bruce M. Psaty; Mark J. Caulfield; Ron M. Krauss; Adrienne L. Cupples; Wouter J. Jukema

doi:10.3389/fphar.2021.679857

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction

Stella Trompet^*
, Iris Postmus
, on behalf of the GIST consortium and the CHARGE pharmacogenetics working group
, Helen R. Warren
, Raymond Noordam
, Roelof A.J. Smit
, Elizabeth Theusch
, Xiaohui Li
, Benoit Arsenault
, Daniel I. Chasman
, Graham A. Hitman
, Patricia B. Munroe
, Jerome I. Rotter
, Bruce M. Psaty
, Mark J. Caulfield
, Ron M. Krauss
, Adrienne L. Cupples
, Wouter J. Jukema

^*Corresponding author for this work

Epidemiology

Leiden University Medical Centre
Barts and The London School of Medicine and Dentistry
NIHR Barts Biomedical Research Centre
University of California at San Francisco
The Lundquist Institute
Université Laval
Harvard Medical School
Hebrew SeniorLife
University of Washington School of Medicine
University of Washington
Boston University School of Public Health
The Framingham Heart Study
Netherlands Heart Institute

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

5 Citations (Scopus)

91 Downloads (Pure)

Abstract

Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10⁻⁴ in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10⁻⁸). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.

Original language	English
Article number	679857
Journal	Frontiers in Pharmacology
Volume	12
DOIs	https://doi.org/10.3389/fphar.2021.679857
Publication status	Published - 5 Jan 2022

Bibliographical note

Funding Information:
The authors declare that this study received funding from Pfizer USA and Bristol-Myers Squibb USA. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. 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, analyzed, 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. 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. CHS. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 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 was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, 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

Publisher Copyright:
Copyright © 2022 Trompet, Postmus, Warren, Noordam, Smit, Theusch, Li, Arsenault, Chasman, Hitman, Munroe, Rotter, Psaty, Caulfield, Krauss, Cupples and Jukema.

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Trompet, S., Postmus, I., on behalf of the GIST consortium and the CHARGE pharmacogenetics working group, Warren, H. R., Noordam, R., Smit, R. A. J., Theusch, E., Li, X., Arsenault, B., Chasman, D. I., Hitman, G. A., Munroe, P. B., Rotter, J. I., Psaty, B. M., Caulfield, M. J., Krauss, R. M., Cupples, A. L., & Jukema, W. J. (2022). The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction. Frontiers in Pharmacology, 12, Article 679857. https://doi.org/10.3389/fphar.2021.679857

@article{666e8294f4b94f1bb72c90a11b41313d,

title = "The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction",

abstract = "Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10−4 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10−8). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.",

author = "Stella Trompet and Iris Postmus and \{on behalf of the GIST consortium and the CHARGE pharmacogenetics working group\} and Warren, \{Helen R.\} and Raymond Noordam and Smit, \{Roelof A.J.\} and Elizabeth Theusch and Xiaohui Li and Benoit Arsenault and Chasman, \{Daniel I.\} and Hitman, \{Graham A.\} and Munroe, \{Patricia B.\} and Rotter, \{Jerome I.\} and Psaty, \{Bruce M.\} and Caulfield, \{Mark J.\} and Krauss, \{Ron M.\} and Cupples, \{Adrienne L.\} and Jukema, \{Wouter J.\}",

note = "Funding Information: The authors declare that this study received funding from Pfizer USA and Bristol-Myers Squibb USA. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. 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, analyzed, 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. 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. CHS. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 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 was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, 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 Publisher Copyright: Copyright {\textcopyright} 2022 Trompet, Postmus, Warren, Noordam, Smit, Theusch, Li, Arsenault, Chasman, Hitman, Munroe, Rotter, Psaty, Caulfield, Krauss, Cupples and Jukema.",

year = "2022",

month = jan,

day = "5",

doi = "10.3389/fphar.2021.679857",

language = "English",

volume = "12",

journal = "Frontiers in Pharmacology",

issn = "1663-9812",

publisher = "Frontiers Media SA",

}

Trompet, S, Postmus, I, on behalf of the GIST consortium and the CHARGE pharmacogenetics working group, Warren, HR, Noordam, R, Smit, RAJ, Theusch, E, Li, X, Arsenault, B, Chasman, DI, Hitman, GA, Munroe, PB, Rotter, JI, Psaty, BM, Caulfield, MJ, Krauss, RM, Cupples, AL & Jukema, WJ 2022, 'The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction', Frontiers in Pharmacology, vol. 12, 679857. https://doi.org/10.3389/fphar.2021.679857

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction. / Trompet, Stella; Postmus, Iris; on behalf of the GIST consortium and the CHARGE pharmacogenetics working group et al.
In: Frontiers in Pharmacology, Vol. 12, 679857, 05.01.2022.

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

TY - JOUR

T1 - The Pharmacogenetics of Statin Therapy on Clinical Events

T2 - No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction

AU - Trompet, Stella

AU - Postmus, Iris

AU - on behalf of the GIST consortium and the CHARGE pharmacogenetics working group

AU - Warren, Helen R.

AU - Noordam, Raymond

AU - Smit, Roelof A.J.

AU - Theusch, Elizabeth

AU - Li, Xiaohui

AU - Arsenault, Benoit

AU - Chasman, Daniel I.

AU - Hitman, Graham A.

AU - Munroe, Patricia B.

AU - Rotter, Jerome I.

AU - Psaty, Bruce M.

AU - Caulfield, Mark J.

AU - Krauss, Ron M.

AU - Cupples, Adrienne L.

AU - Jukema, Wouter J.

N1 - Funding Information: The authors declare that this study received funding from Pfizer USA and Bristol-Myers Squibb USA. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. 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, analyzed, 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. 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. CHS. This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, 75N92021D00006; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 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 was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, 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 Publisher Copyright: Copyright © 2022 Trompet, Postmus, Warren, Noordam, Smit, Theusch, Li, Arsenault, Chasman, Hitman, Munroe, Rotter, Psaty, Caulfield, Krauss, Cupples and Jukema.

PY - 2022/1/5

Y1 - 2022/1/5

N2 - Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10−4 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10−8). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.

AB - Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10−4 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10−8). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.

UR - https://www.scopus.com/pages/publications/85123314106

U2 - 10.3389/fphar.2021.679857

DO - 10.3389/fphar.2021.679857

M3 - Article

C2 - 35069183

AN - SCOPUS:85123314106

SN - 1663-9812

VL - 12

JO - Frontiers in Pharmacology

JF - Frontiers in Pharmacology

M1 - 679857

ER -

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction

Abstract

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