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A Method to Study the C924T Polymorphism of the Thromboxane A2 Receptor Gene
Published on: April 1, 2019
Association of ABCC2 polymorphism with clopidogrel response in Chinese patients undergoing percutaneous coronary
Lida Chen1, Chao Zheng1, Mengmeng Hao1
1Department of Blood Transfusion, China-Japan Friendship Hospital, Beijing, China.
Insights
The ABCC2 rs717620 polymorphism, particularly the TT allele, is linked to clopidogrel hyperreactivity in patients with coronary artery disease. This finding, alongside CYP2C19 variants, offers new insights for personalized clopidogrel therapy.
Area of Science:
- Pharmacogenomics
- Cardiovascular Medicine
- Molecular Biology
Background:
- Clopidogrel response varies significantly among individuals, impacting treatment efficacy.
- Genetic factors, including polymorphisms in drug-metabolizing enzymes and transporters, are known to influence clopidogrel pharmacodynamics.
- Understanding these genetic associations is crucial for optimizing antiplatelet therapy in patients with coronary artery disease (CAD).
Purpose of the Study:
- To investigate the association between ABCC2 gene polymorphisms and clopidogrel response in Chinese CAD patients.
- To explore the potential mechanisms underlying this association, including interactions with CYP2C19.
- To identify novel genetic targets for predicting and managing individual responses to clopidogrel.
Main Methods:
- Genotyping of ABCC2 (rs717620, rs2273697, rs3740066) and CYP2C19 (*2, *3) polymorphisms using HRM-PCR and real-time PCR.
- Determination of ADP-induced platelet inhibition rates (PAIR%) via thromboelastometry in 213 Chinese CAD patients undergoing percutaneous coronary intervention (PCI).
- Statistical analysis to assess the correlation between genotypes and clopidogrel response, adjusting for confounding factors.
Main Results:
- The ABCC2 rs717620 TT genotype was significantly associated with higher platelet inhibition rates (hyperreactivity) compared to CT and CC genotypes.
- CYP2C19*2 and *3 polymorphisms were linked to lower platelet inhibition rates (resistance).
- In extensive metabolizers, TT carriers showed higher PAIR%, while in poor metabolizers, CC carriers showed lower PAIR%, suggesting gene-gene interactions.
Conclusions:
- ABCC2 rs717620 represents a novel genetic target influencing clopidogrel response, with the TT allele predicting hyperreactivity.
- CYP2C19*2 and *3 are associated with clopidogrel resistance.
- ABCC2 rs717620 may modulate clopidogrel response through post-transcriptional regulation and interaction with CYP2C19, providing insights for personalized antiplatelet therapy.
Abstract:
Aim: In this study, we investigated the association between ABCC2 polymorphism and clopidogrel response as well as the associated hypothetical mechanism. Methods: Chinese patients (213) with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) and received clopidogrel were recruited. Thereafter, their ADP-induced platelet inhibition rates (PAIR%) were determined via thromboelastometry. Further, the single-nucleotide polymorphisms (SNPs) of ABCC2 were genotyped using high-resolution melting curve (HRM)-PCR, while CYP2C19*2 and *3 polymorphisms were genotyped via real-time PCR. Results: The allele frequencies of ABCC2 rs717620 were 74.88 and 25.12% for the C and T alleles, respectively. Further, ABCC2 rs717620 TT carriers exhibited significantly higher PAIR% values (72.60 ± 27.69) than both CT (61.44 ± 23.65) and CC carriers (52.72 ± 21.99) (p = 0.047 and p = 0.001, respectively), and ABCC2 rs717620 CT carriers showed significantly higher mean PAIR% values than ABCC2 rs717620 CC carriers (p = 0.011). However, the PAIR% values corresponding to ABCC2 rs2273697 and ABCC2 rs3740066 carriers were not different. Additionally, CYP2C19*2 AA carriers presented significantly lower PAIR% values than CYP2C19*2 GA (p = 0.015) and GG (p = 0.003) carriers, and CYP2C19*3 GA carriers also presented significantly lower PAIR% values than CYP2C19*3 GG carriers (p = 0.041). In patients with CYP2C19 extensive metabolizers (EM), ABCC2 rs717620 TT carriers showed significantly higher PAIR% values (89.77 ± 9.73) than CT (76.76 ± 26.00) and CC carriers (74.09 ± 25.29) (p = 0.040 and p = 0.009, respectively). In patients with CYP2C19 poor metabolizers (PM), ABCC2 rs717620 CC carriers showed significantly lower PAIR% values (51.72 ± 25.78) than CT carriers (75.37 ± 23.57) (p = 0.043). Furthermore, after adjusting for confounding factors, ABCC2 rs717620 was identified as a strong predictor of clopidogrel hyperreactivity. Conclusion: We proposed a new target, ABCC2 rs717620, in the efflux pathway that affects individual responses to clopidogrel. The TT allele of ABCC2 rs717620 was also identified as an independent risk factor for clopidogrel hyperreactivity, and CYP2C19*2 and *3 showed association with an increased risk for clopidogrel resistance. Additionally, ABCC2 rs717620 may affect individual responses to clopidogrel via post-transcriptional regulation and interaction with CYP2C19. These findings provide new insights that may guide the accurate use of clopidogrel.
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