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. 2020 Sep 11;11(9):1068.
doi: 10.3390/genes11091068.

Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention

Thomas O Bergmeijer  1 , Alfi Yasmina  2   3 , Gerrit J A Vos  1 , Paul W A Janssen  1 , Christian M Hackeng  4 , Johannes C Kelder  1 , Shefali S Verma  5 , Marylyn D Ritchie  6 , Li Gong  7 , Teri E Klein  7 , Icpc Investigators, Anthonius de Boer  2 , Olaf H Klungel  2 , Jurriën M Ten Berg  1 , Vera H M Deneer  2   8
Affiliations

Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention

Thomas O Bergmeijer et al. Genes (Basel). .

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 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.

Keywords: CYP3A4; PCI; PPAR; clopidogrel; fibrate; genotyping; personalized medicine; pharmacogenomics; statin.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
The on-treatment platelet reactivity, as measured with the VerifyNow® P2Y12 assay for CYP3A4*22 (A), PPAR-α G209A (B), and PPAR-α A208G (C).
Figure 2
Figure 2
Meta-analysis for G209A and A208G variants in the main analysis and the POPular and ICPC validation cohorts. CI = confidence interval, SMD = standardized mean difference. For the meta-analysis, a random effects model was used.
See this image and copyright information in PMC

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