PPAR-α genetic variants influence on-treatment platelet reactivity in patients treated with clopidogrel and lipid-lowering drugs and undergoing non-urgent percutaneous coronary intervention with stent implantation

Background: Response to clopidogrel varies between patients, due to many factors, like polymorphisms in genes encoding for metabolizing enzymes. The CYP3A4∗22 polymorphism has been proven to decrease the expression of CYP3A4, while the PPAR-α genetic variants G209A and A208G have been identified as determinants that affect CYP3A4. Statins and fibrates, which are the ligands of PPAR-α as well as being metabolized by CYP3A4, might also affect the response of clopidogrel through these two proteins. Objectives: To investigate the association between on-treatment platelet reactivity and the CYP3A4∗22 allele and genetic variations of the PPAR-α genes in clopidogrel-treated patients undergoing non-urgent percutaneous coronary intervention (PCI) with stenting and to evaluate the influence of statin/fibrate co-medication on these associations. Methods: A total of 1126 patients with non-urgent PCI and stenting pre-treated with clopidogrel and aspirin were genotyped for CYP3A4∗22 and PPAR-α (G209A and A208G). Platelet reactivity was measured using the VerifyNow® P2Y12-assay, expressed in PRU. Multivariate linear regression analysis was used to assess the association between the genetic variants and platelet reactivity, adjusted for confounders, including the CYP2C19 metabolizer status. A stratified analysis was conducted for patients with statin/fibrate co-medication. A recessive model was used for all associations. Results: The CYP3A4∗22/∗22 genotype was present in 0.4% of patients, 6.8% had the PPAR-α G209A AA genotype, and 7.0% had the PPAR-α A208G GG genotype. CYP3A4∗22 was not associated with platelet reactivity. PPAR-α genetic variants were significantly associated with platelet reactivity (PPAR-α G209A AA: -23.87 PRU [-43.54, -4.19]; PPAR-α A208G GG: -23.70 PRU [-43.13, -4.27]). In patients who were on statin/fibrate co-medication, these PPAR-α genetic variants were associated with an even lower platelet reactivity (-29.74 PRU [-50.94, -8.54], and -29.38 PRU [-50.26, -8.49], respectively), while those without statin/fibrate co-medication did not show a significant change in platelet reactivity (13.00 PRU [-39.79, 65.80]). Conclusions: Two genetic variants in PPAR-α (G209A and A208G) were associated with lower platelet reactivity in patients with non-urgent PCI and stenting co-treated with clopidogrel and lipid-lowering drugs.