Association of ABCB1, CYP3A5, and P2Y12 Gene Polymorphisms with Platelet Reactivity in Clopidogrel-Treated Patients

Objectives: To evaluate the association of these genetic variants with clopidogrel response variability in post percutaneous coronary intervention patients, as well as to examine their genotype distribution.

Method: An exploratory, cross-sectional study was conducted using archived blood samples from antiplatelet-naïve patients who received clopidogrel after PCI at Hospital Pulau Pinang between August 2021 and August 2022. Genotyping of P2Y12, CYP3A5 were performed using amplification refractory mutation system polymerase chain reaction (ARMS-PCR) and ABCB1 using real-time PCR. Platelet reactivity index (PRI), assessed by ELISA-VASP method, was used to determine the response status.

Results: A total of 30 subjects were enrolled in the study, with 16 (53.3%) classified as clopidogrel responders and 14 (46.7%) as non-responders. The frequencies of variant genotypes observed were 3.33% for P2Y12 rs2046934 (GG), 13.3% for both rs6785930 (AA) and rs6809699 (CC), 36.7% for CYP3A5 rs776746 (CC) and 20.0% for ABCB1 rs1045642. The mean value of the measured PRI was 50.33 (± 17.91, 95% CI: 43.64-57.02). Significant associations with increased platelet reactivity were observed for P2Y12 rs2046934 (dominant model, p=0.013), P2Y12 rs6809699 (dominant model, p=0.041), and ABCB1 variants (recessive model, p=0.039). However, after stratification by CYP2C19 genotype, only P2Y12 rs6809699 remained significantly associated with PRI (p=0.042), suggesting a potential role in modulating clopidogrel response at the receptor level.

Conclusions: The P2Y12 rs6809699 genotype was associated with higher on-treatment platelet reactivity, independent of CYP2C19 genotype, suggesting its potential as a genetic marker for clopidogrel resistance. Further studies with larger sample sizes are needed to assess its clinical utility.