Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans.
Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450 (CYP) isoenzymes to inhibit platelet aggregation. Individual variability of platelet inhibition by clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness. In this study, we sought to determine the relation of genetic polymorphisms of CYP genes to clopidogrel resistance in Koreans. Four hundred fifty patients who underwent successful percutaneous coronary intervention with drug-eluting stents were randomly assigned to treatment with dual antiplatelet regimen (aspirin plus clopidogrel) or triple antiplatelet regimen (aspirin plus clopidogrel plus cilostazol). Clopidogrel resistance using VerifyNow P2Y12 assay and genetic analysis were performed in 387 patients. Clopidogrel resistance was found in 112 patients (28.9%). In the clopidogrel-responsive group, there was a significantly higher proportion of cilostazol use. Because cilostazol showed a significant influence on clopidogrel resistance, we examined the association of single-nucleotide polymorphisms and clopidogrel resistance in the dual and triple antiplatelet therapy groups, respectively. In all subjects, the CYP2C19*3A allele was significantly more prevalent in the clopidogrel-resistant group compared with the clopidogrel-responsive group. Multiple logistic regression analysis demonstrated that CYP2C19*3 is an independent predictor of clopidogrel resistance. In conclusion, CYP2C19*3 single-nucleotide polymorphisms is an independent risk factor of clopidogrel resistance in Korean subjects with coronary artery disease.
Lee
Jung Myung
JM
Division of Cardiology, Cardiovascular Genome Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Park
Sungha
S
Shin
Dong-Jik
DJ
Choi
Donghoon
D
Shim
Chi Young
CY
Ko
Young-Guk
YG
Kim
Jung-Sun
JS
Shin
Eun-Soon
ES
Chang
Chong Won
CW
Lee
Jong-Eun
JE
Jang
Yangsoo
Y
D015906:Angioplasty, Balloon, Coronary; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000077407:Cilostazol; D000077144:Clopidogrel; D016001:Confidence Intervals; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D006801:Humans; D007723:Korea / Q000453:epidemiology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000077407:Cilostazol; D013988:Ticlopidine