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Published on: April 1, 2019
Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing
Alba Antúnez-Rodríguez1,2, Sonia García-Rodríguez1, Ana Pozo-Agundo1,2
1Center for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Junta de Andalucía, Avenida de la Ilustración 114, 18016 Granada, Spain.
Insights
Genetic factors influence clopidogrel response in acute coronary syndrome patients. New variants, like ABCA1, may predict cardiovascular events beyond CYP2C19, improving antiplatelet therapy guidance.
Area of Science:
- Pharmacogenomics
- Cardiovascular Genetics
- Drug Metabolism
Background:
- Clopidogrel is a key antiplatelet drug for acute coronary syndrome (ACS) patients post-percutaneous coronary intervention (PCI).
- Variability in clopidogrel response is linked to genetic factors, notably CYP2C19 loss-of-function alleles, increasing major adverse cardiovascular event (MACE) risk.
- Despite CYP2C19 genotype-guided therapy, MACEs persist, suggesting other genetic factors contribute to therapeutic failure.
Purpose of the Study:
- To identify novel genetic variants associated with adverse cardiovascular events in ACS-PCI patients despite pharmacogenomic-guided antiplatelet therapy.
- To explore the role of disease predisposition genes in clopidogrel non-response.
- To develop improved predictive models for cardiovascular events.
Main Methods:
- A custom sequencing panel was used to analyze genetic variants in 244 ACS-PCI-stent patients and 99 controls.
- Association analysis was performed, considering treatment groups (clopidogrel vs. prasugrel).
- Random forest models were employed to predict risk and assess the predictive power of identified variants.
Main Results:
- No single polymorphism reached genome-wide significance.
- In clopidogrel-treated patients, the rs2472434 variant in ABCA1 (lipid metabolism) showed a strong association with secondary cardiovascular events (p = 1.7 × 10⁻³).
- Predictive models incorporating variants from clopidogrel pathways (CYP2C19, ABCB1, UGT2B7) and ABCA1 discriminated between patients with and without events (p = 0.02445).
Conclusions:
- Combined genotyping of CYP2C19 loss-of-function and ABCB1 C3435T variants can aid antiplatelet therapy guidance.
- Novel targets like rs2472434 (ABCA1) and rs7439366 (UGT2B7) may enhance cardiovascular event risk prediction.
- Unexplained clopidogrel variability might stem from disease pathogenesis, necessitating a paradigm shift in pharmacogenomic research.
Abstract:
Clopidogrel is widely used as an antiplatelet therapy for acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Genetic factors influence variability in clopidogrel response, with non-functional CYP2C19 alleles increasing the risk of major adverse cardiovascular events (MACEs). While CYP2C19 genotype-guided therapy after PCI improves outcomes, MACEs persist at variable rates. Pharmacogenomics (PGx) has primarily focused on genes related to drug metabolism, but therapeutic failure may stem from individual disease predisposition. This study aims to identify novel genetic variants underlying adverse events after PCI despite PGx-guided therapy. A custom sequencing panel was analyzed in 244 ACS-PCI-stent patients and 99 controls without cardiovascular (CV) disease. Association analysis was performed independent of treatment and by prescribed treatment (clopidogrel or prasugrel), complemented by random forest models to predict risk during antiplatelet therapy. No polymorphism reached genomic significance, but in clopidogrel-treated patients, rs2472434 in ABCA1, related to altered lipid metabolism, was strongly associated with secondary CV events (p = 1.7 × 10-3). Variants in the clopidogrel pathway, including CYP2C19, ABCB1, and UGT2B7, were also identified and may influence clopidogrel response. Predictive models incorporating these variants effectively discriminated patients with and without events (p = 0.02445). Our findings support combined genotyping of CYP2C19 loss-of-function and ABCB1 C3435T variants to guide antiplatelet therapy and suggest additional targets, such as rs2472434 (ABCA1) and rs7439366 (UGT2B7), to improve risk prediction of adverse CV events. Therefore, the unexplained variability in clopidogrel response may be due to disease pathogenesis itself, highlighting the need for a paradigm shift in PGx studies.
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