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Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population

  • Pharmacogenetics
  • Published:
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Abstract

Background

The antiplatelet activity of clopidogrel is variable among patients suffering from ischemic heart disease. Variation in the cytochrome P450 2C19 (CYP2C19) gene coding for the CYP2C19 enzyme is one of the major determinants of this variable response to clopidogrel. The activity of the CYP2C19 enzyme, which plays a role in the conversion of the prodrug clopidogrel to its active metabolite, is genetically influenced by polymorphisms in its gene. The aim of our study was to evaluate the association of CYP2C19 polymorphisms and the antiplatelet effect of clopidogrel in the South Indian Tamilian population.

Materials and methods

Genotyping and platelet aggregation results of 149 ischemic heart disease patients on clopidogrel maintenance therapy (75 mg daily dose) were analyzed in this study. CYP2C19 polymorphisms were genotyped by the PCR-restriction fragment length polymorphism method. We measured residual platelet activities in these patients on clopidogrel therapy in terms of impedance (expressed as ohms). The study subjects were divided into two metabolizer phenotype groups [group 1: poor/intermediate metabolizers (PM/IM); group 2: extensive/ultra-rapid metabolizers (EM/URM)] based on CYP2C19 genotype, and the residual platelet activities were compared. Higher values of impedance denote increased residual platelet activity.

Results

Poor/intermediate metabolizers had significantly higher impedance values than EM/URM [(median; range) 4.0; 0–13 vs. 2.0; 0–11, respectively; p = 0.04]. These higher impedance values denote higher residual platelet activities among the carriers of loss-of-function alleles (CYP2C19*2,*3) than among non-carriers. However, residual platelet activities were lower among the carriers of the gain-of-function allele (CYP2C19*17) than among non-carriers, although this difference was not significant.

Conclusion

Patients with CYP2C19 (*2 or *3) genetic polymorphisms had higher residual platelet activities and were associated with a reduced antiplatelet response to clopidogrel. As the South Indian Tamilian population is characterized with higher frequencies of these genetic polymorphisms, our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy.

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Acknowledgments

The work was undertaken in the ICMR Center for Advance Research in Pharmacogenomics of the Department of Pharmacology, JIPMER, India. The center received funding from the Indian Council of Medical Research (ICMR), India. We also acknowledge JIPMER for funding this project. We thank Ms. Immaculate, Mr. Rajan, Ms. T. Priyatharsini, Ms. Saraswathi, and Ms. Indumathi for their technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, ICMR Centre for Advance Research in Pharmacogenomics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India

    K. Subraja, S. A. Dkhar, R. Priyadharsini, B. K. Ravindra, D. G. Shewade & C. Adithan

  2. Department of Cardiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India

    S. Satheesh

  3. Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India

    M. G. Sridhar

  4. Department of Neurology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006, India

    S. K. Narayan

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  1. K. Subraja
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Correspondence to S. A. Dkhar.

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Subraja, K., Dkhar, S.A., Priyadharsini, R. et al. Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population. Eur J Clin Pharmacol 69, 415–422 (2013). https://doi.org/10.1007/s00228-012-1381-8

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  • DOI: https://doi.org/10.1007/s00228-012-1381-8

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