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Article

Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent

by
Alba Antúnez-Rodríguez
1,2,
Sonia García-Rodríguez
1,
Ana Pozo-Agundo
1,2,
Jesús Gabriel Sánchez-Ramos
3,
Eduardo Moreno-Escobar
3,
José Matías Triviño-Juárez
4,
María Jesús Álvarez-Cubero
1,2,5,
Luis Javier Martínez-González
1,5 and
Cristina Lucía Dávila-Fajardo
1,2,6,*
1
Center for Genomics and Oncological Research (GENYO), Pfizer—University of Granada—Junta de Andalucía, Avenida de la Ilustración 114, 18016 Granada, Spain
2
Instituto de Investigación Biosanitaria (ibs.GRANADA), Avenida de Madrid 15, Pabellón de Consultas Externas, 2ª Planta (Antigua Área de Dirección), 18012 Granada, Spain
3
Cardiology Department, Hospital Universitario Clínico San Cecilio, Avenida de la Innovación s/n, 18016 Granada, Spain
4
Department of Radiology and Physical Medicine, Faculty of Medicine, University of Granada, Avenida Doctor Jesús Candel Fábregas 11, 18016 Granada, Spain
5
Department of Biochemistry and Molecular Biology III and Inmunology, Faculty of Medicine, University of Granada, Avenida Doctor Jesús Candel Fábregas 11, 18016 Granada, Spain
6
Pharmacy Department, Hospital Universitario Virgen de las Nieves, Avenida de las Fuerzas Armadas 2, 18014 Granada, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(19), 9766; https://doi.org/10.3390/ijms26199766
Submission received: 21 August 2025 / Revised: 29 September 2025 / Accepted: 6 October 2025 / Published: 7 October 2025
(This article belongs to the Special Issue Molecular and Translational Research in Cardiovascular Endocrinology, Cardio-Metabolic Diseases and Non-Alcoholic Fatty Liver Disease (NAFLD): 2nd Edition)
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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.
Keywords: dual antiplatelet therapy; cardiovascular drugs; acute coronary syndrome; clopidogrel response; atherosclerosis; pharmacogenomics; personalized medicine dual antiplatelet therapy; cardiovascular drugs; acute coronary syndrome; clopidogrel response; atherosclerosis; pharmacogenomics; personalized medicine
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MDPI and ACS Style

Antúnez-Rodríguez, A.; García-Rodríguez, S.; Pozo-Agundo, A.; Sánchez-Ramos, J.G.; Moreno-Escobar, E.; Triviño-Juárez, J.M.; Álvarez-Cubero, M.J.; Martínez-González, L.J.; Dávila-Fajardo, C.L. Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent. Int. J. Mol. Sci. 2025, 26, 9766. https://doi.org/10.3390/ijms26199766

AMA Style

Antúnez-Rodríguez A, García-Rodríguez S, Pozo-Agundo A, Sánchez-Ramos JG, Moreno-Escobar E, Triviño-Juárez JM, Álvarez-Cubero MJ, Martínez-González LJ, Dávila-Fajardo CL. Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent. International Journal of Molecular Sciences. 2025; 26(19):9766. https://doi.org/10.3390/ijms26199766

Chicago/Turabian Style

Antúnez-Rodríguez, Alba, Sonia García-Rodríguez, Ana Pozo-Agundo, Jesús Gabriel Sánchez-Ramos, Eduardo Moreno-Escobar, José Matías Triviño-Juárez, María Jesús Álvarez-Cubero, Luis Javier Martínez-González, and Cristina Lucía Dávila-Fajardo. 2025. "Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent" International Journal of Molecular Sciences 26, no. 19: 9766. https://doi.org/10.3390/ijms26199766

APA Style

Antúnez-Rodríguez, A., García-Rodríguez, S., Pozo-Agundo, A., Sánchez-Ramos, J. G., Moreno-Escobar, E., Triviño-Juárez, J. M., Álvarez-Cubero, M. J., Martínez-González, L. J., & Dávila-Fajardo, C. L. (2025). Custom Gene Panel Analysis Identifies Novel Polymorphisms Associated with Clopidogrel Response in Patients Undergoing Percutaneous Coronary Intervention with Stent. International Journal of Molecular Sciences, 26(19), 9766. https://doi.org/10.3390/ijms26199766

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