Effect ofCYP3A4*22 andPPAR-alpha Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention
ICPC investigators
(2020) Genes, volume 11, issue 9, pp. 1 - 13
(Article)
Abstract
This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom
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CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016; A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.
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Keywords: Clopidogrel, CYP3A4, Fibrate, Genotyping, PCI, Personalized medicine, Pharmacogenomics, PPAR, Statin, clopidogrel, genotyping, personalized medicine, pharmacogenomics, statin, fibrate, Genetics(clinical), Genetics, Journal Article
ISSN: 2073-4425
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: Funding Information: This work was supported by the St Antonius Innovation fund and a ZonMw TopZorg grant. ZonMw is a Dutch organization funded by the government promoting health care research and the implementation of study results in daily practice. The International Clopidogrel Pharmacogenomics Consortium was supported by NIH [grant numbers U01 HL105198, R24 GM61374], and the Robert Bosch Stiftung Stuttgart, Germany Acknowledgments: We thank Richard van de Heide, Remko Harms, Sylvia van der Steen van Vuren, Tamimount el Dahri, and Kees de Bruijn from the Pharmacogenetics, Pharmaceutical and Toxicological Laboratory of the Department of Clinical Pharmacy for their work in genotyping. We thank the participating centers of the ICPC for their contribution to this analysis in sharing data for the validation cohort and evaluation of the manuscript (full author list included in the supplementary data). Funding Information: Conflicts of Interest: J.B. and P.J. received funding from ZonMW TopZorg grant for a part of the submitted study. The Division of Pharmacoepidemiology and Clinical Pharmacology employing authors A.B. and O.K. has received unrestricted funding for pharmacoepidemiological research from GlaxoSmithKline, the private-public funded Top Institute Pharma, and the EU Innovative medicines Initiate (IMI). A.Y. received a scholarship for her doctorate degree from the Dikti-Neso Scholarship Award from the Directorate General of Higher Education, Ministry of Education and Culture, Indonesia. M.R. received travel/consulting/speaker fees from Cipherome, Goldfinch, DNAnexus, and the American Society of Health System Pharmacists. The other co-authors do not have any conflicts of interest to disclose. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Funding Information: Funding: This work was supported by the St Antonius Innovation fund and a ZonMw TopZorg grant. ZonMw is a Dutch organization funded by the government promoting health care research and the implementation of study results in daily practice. The International Clopidogrel Pharmacogenomics Consortium was supported by NIH [grant numbers U01 HL105198, R24 GM61374], and the Robert Bosch Stiftung Stuttgart, Germany Acknowledgments: We thank Richard van de Heide, Remko Harms, Sylvia van der Steen van Vuren, Tamimount el Dahri, and Kees de Bruijn from the Pharmacogenetics, Pharmaceutical and Toxicological Laboratory of the Department of Clinical Pharmacy for their work in genotyping. We thank the participating centers of the ICPC for their contribution to this analysis in sharing data for the validation cohort and evaluation of the manuscript (full author list included in the supplementary data). Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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