European Journal of Clinical Pharmacology

, Volume 74, Issue 4, pp 443–451 | Cite as

Analysis of the CYP2C19 genotype associated with bleeding in Serbian STEMI patients who have undergone primary PCI and treatment with clopidogrel

  • Mirjana Novkovic
  • Dragan Matic
  • Jelena Kusic-Tisma
  • Nebojsa Antonijevic
  • Dragica Radojkovic
  • Ljiljana RakicevicEmail author



Bleeding is one of the possible adverse events during clopidogrel therapy. The CYP2C19 gene is the most significant genetic factor which influences response to clopidogrel treatment. We aimed to examine the contribution of the CYP2C19 gene to bleeding occurrence during clopidogrel therapy in Serbian patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).


This case–control study included 53 patients who experienced bleeding and 55 patients without bleeding. Bleeding events were defined and classified using the Bleeding Academic Research Consortium (BARC) criteria. All patients were prescribed daily doses of clopidogrel during the 1-year follow-up after PCI. The CYP2C19*17 (c.-806C>T, rs12248560), rs11568732 (c.-889T>G, CYP2C19*20), CYP2C19*2 (c.681G>A; rs4244285) and CYP2C19*3 (c.636G>A; rs4986893) variants were analysed in all 108 patients. Additionally, sequencing of all nine exons, 5′UTR and 3′UTR in the rs11568732 carriers was performed.


Association between bleeding (BARC type ≥ 2) and the CYP2C19*17 variant was not observed [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.2–1.1; p = 0.107). The rs11568732 variant showed significant association with bleeding (OR, 3.7; 95% CI, 1.12–12.44; p = 0.025). Also, we found that the rs11568732 variant appears independently of haplotype CYP2C19*3B, which is contrary to the previous findings.


Our results indicate the absence of CYP2C19*17 influence and turn the attention to the potential significance of the rs11568732 variant in terms of adverse effects of clopidogrel. However, it is necessary to conduct an independent conformation study in order to verify this finding. Also, an analysis of the functional implication of the rs11568732 variant is necessary in order to confirm the significance of this variant, both in relation to its influence on gene expression and in relation to its medical significance.


CYP2C19 Clopidogrel PCI Bleeding Pharmacogenetics 



The authors deeply appreciate the contributions of all clinical/research staff involved in the present study. This work was supported by grant 173008 from the Ministry of Education, Science and Technological Development, Republic of Serbia.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.

Supplementary material

228_2017_2401_MOESM1_ESM.pdf (85 kb)
Supplementary Table 1 (PDF 84 kb)
228_2017_2401_MOESM2_ESM.pdf (143 kb)
Supplementary Table 2 (PDF 142 kb)
228_2017_2401_MOESM3_ESM.pdf (219 kb)
Supplementary Table 3 (PDF 219 kb)
228_2017_2401_MOESM4_ESM.pdf (303 kb)
Supplementary Table 4 (PDF 303 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017
corrected publication February/2018

Authors and Affiliations

  • Mirjana Novkovic
    • 1
  • Dragan Matic
    • 2
    • 3
  • Jelena Kusic-Tisma
    • 1
  • Nebojsa Antonijevic
    • 2
    • 3
  • Dragica Radojkovic
    • 1
  • Ljiljana Rakicevic
    • 1
    Email author
  1. 1.Institute of Molecular Genetics and Genetic EngineeringUniversity of BelgradeBelgradeSerbia
  2. 2.Emergency Department, Clinic for CardiologyClinical Center of SerbiaBelgradeSerbia
  3. 3.Faculty of MedicineUniversity of BelgradeBelgradeSerbia

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