Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico

Félix R. Cedillo-Salazar; Lizeth Martínez-Jacobo; Yadira X. Pérez-Páramo; Ricardo Cerda-Flores; Laura E. Martínez; José C. Jaime-Pérez; María G. Moreno-Treviño; Edelmiro Pérez-Rodríguez; Francisco J. Bosques-Padilla; Montserrat Cedillo-Avila; María A. Cedillo-Avila; Michelle Zamudio-Osuna

doi:10.24875/ACM.19000033

Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico

Título traducido de la contribución: Asociación del polimorfismo CYP2C19*2 con resistencia a clopidogrel en pacientes con alto riesgo cardiovascular en el noreste de México

Félix R. Cedillo-Salazar, Lizeth Martínez-Jacobo, Yadira X. Pérez-Páramo, Ricardo Cerda-Flores, Laura E. Martínez, José C. Jaime-Pérez, María G. Moreno-Treviño, Edelmiro Pérez-Rodríguez, Francisco J. Bosques-Padilla, Montserrat Cedillo-Avila, María A. Cedillo-Avila, Michelle Zamudio-Osuna

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5 Citas (Scopus)

Resumen

Objetivo: Los antiplaquetarios orales son clave en la farmacoterapia moderna de las enfermedades aterotrombóticas cardiovasculares. Clopidogrel (CLO) constituye el principal tratamiento preventivo de aterotrombosis (AT). Sin embargo, se ha documentado una considerable variación interindividual en la respuesta a CLO, lo que da como resultado una terapia subóptima y mayor riesgo de efectos adversos en algunos pacientes. La enzima CYP2C19 es la isoforma CYP que activa CLO a su metabolito activo. Se han identificado varios polimorfismos de un solo nucleótido en el gen CYP2C19 como fuertes predictores de respuesta farmacológica alterada a CLO. Al menos 16 variantes se han asociado con cambios en la actividad de CYP2C19.

Método: Se reclutaron un total de 102 sujetos con alto riesgo cardiovascular del noreste de México, con dosis de mantenimiento de 75 mg de CLO/día. La reactividad plaquetaria se midió con el ensayo Verify Now P2Y12, la presencia de CYP2C19*2 se identificó mediante polymerase chain reaction en tiempo real.

Resultado: Los pacientes fueron clasificados por el estado metabolizador CYP2C19*2 utilizando nomenclatura consenso, como metabolizador normal (G/G), metabolizador intermedio (G/A) y metabolizador pobre (A/A), respectivamente. La frecuencia del fenotipo para CYP2C19*2 fue 74.5% (G/G), 21.6% (G/A) y 3.9% (A/A). Los sujetos con alelo A presentaron ≥235 niveles P2Y12 reaction unit, clasificándolos como metabolizadores deficientes. La prevalencia de eficacia reducida a CLO se asoció con la presencia del polimorfismo CYP2C19*2 en pacientes mexicanos.

Conclusiones: La presencia del alelo CYP2C19*2 se relaciona con resistencia al efecto antiagregante plaquetario del CLO (p = 0.003).

Palabras Clave: CYP2C19*2. Clopidogrel. Alto riesgo cardiovascular. Polimorfismo. Resistencia. Alelo

Título traducido de la contribución	Asociación del polimorfismo CYP2C19*2 con resistencia a clopidogrel en pacientes con alto riesgo cardiovascular en el noreste de México
Idioma original	English
Páginas (desde-hasta)	324-329
Número de páginas	6
Publicación	Archivos de Cardiologia de Mexico
Volumen	89
N.º	4
DOI	https://doi.org/10.24875/ACM.19000033
Estado	Published - 1 oct 2019

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Publisher Copyright:
© 2019 Instituto Nacional de Cardiología Ignacio Chávez.

All Science Journal Classification (ASJC) codes

Cardiología y medicina cardiovascular

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10.24875/ACM.19000033

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Cedillo-Salazar, F. R., Martínez-Jacobo, L., Pérez-Páramo, Y. X., Cerda-Flores, R., Martínez, L. E., Jaime-Pérez, J. C., Moreno-Treviño, M. G., Pérez-Rodríguez, E., Bosques-Padilla, F. J., Cedillo-Avila, M., Cedillo-Avila, M. A., & Zamudio-Osuna, M. (2019). Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico. Archivos de Cardiologia de Mexico, 89(4), 324-329. https://doi.org/10.24875/ACM.19000033

@article{62118a71c0a64863b8f851d5ab0daf8e,

title = "Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico",

abstract = "Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).",

author = "Cedillo-Salazar, {F{\'e}lix R.} and Lizeth Mart{\'i}nez-Jacobo and P{\'e}rez-P{\'a}ramo, {Yadira X.} and Ricardo Cerda-Flores and Mart{\'i}nez, {Laura E.} and Jaime-P{\'e}rez, {Jos{\'e} C.} and Moreno-Trevi{\~n}o, {Mar{\'i}a G.} and Edelmiro P{\'e}rez-Rodr{\'i}guez and Bosques-Padilla, {Francisco J.} and Montserrat Cedillo-Avila and Cedillo-Avila, {Mar{\'i}a A.} and Michelle Zamudio-Osuna",

note = "Publisher Copyright: {\textcopyright} 2019 Instituto Nacional de Cardiolog{\'i}a Ignacio Ch{\'a}vez.",

year = "2019",

month = oct,

day = "1",

doi = "10.24875/ACM.19000033",

language = "English",

volume = "89",

pages = "324--329",

journal = "Archivos de Cardiologia de Mexico",

issn = "1405-9940",

publisher = "Instituto Nacional de Cardiologia Ignazio Chavez",

number = "4",

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Cedillo-Salazar, FR, Martínez-Jacobo, L, Pérez-Páramo, YX, Cerda-Flores, R, Martínez, LE, Jaime-Pérez, JC, Moreno-Treviño, MG, Pérez-Rodríguez, E, Bosques-Padilla, FJ, Cedillo-Avila, M, Cedillo-Avila, MA & Zamudio-Osuna, M 2019, 'Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico', Archivos de Cardiologia de Mexico, vol. 89, n.º 4, pp. 324-329. https://doi.org/10.24875/ACM.19000033

TY - JOUR

T1 - Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico

AU - Cedillo-Salazar, Félix R.

AU - Martínez-Jacobo, Lizeth

AU - Pérez-Páramo, Yadira X.

AU - Cerda-Flores, Ricardo

AU - Martínez, Laura E.

AU - Jaime-Pérez, José C.

AU - Moreno-Treviño, María G.

AU - Pérez-Rodríguez, Edelmiro

AU - Bosques-Padilla, Francisco J.

AU - Cedillo-Avila, Montserrat

AU - Cedillo-Avila, María A.

AU - Zamudio-Osuna, Michelle

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).

AB - Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).

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Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico

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