Association of CYP2C19 Polymorphism with Clopidogrel Resistance in Patients with Acute Coronary Syndrome in China

Abstract

BackgroundThe relationship between clopidogrel-resistance (CR) and polymorphism located in genes encoding clopidogrel metabolism-related enzymes has not been fully explored. Thus far, few studies on CR-associated polymorphism have been conducted in the Chinese population. The purpose of this study was to identify CYP2C19 polymorphism associated with CR in patients with acute coronary syndrome in China.Material/MethodsThere were 125 patients with acute coronary syndromes (ACS) selected for this study. Of these, 27 patients (21.6%) showed CR (less than 10% reduction in platelet accumulation rate), while the remaining 98 patients (78.4%) were non-clopidogrel-resistant (NCR).ResultsThere were significant differences in the allele frequencies of CYP2C19 (rs4244285) (P=0.03) and CYP2C19 (rs4986893) (P=0.005) between the 2 groups; however, there was no significant difference in allele frequencies of ABCB1 (rs1045642) (P=0.661) and PON1 (rs662) (P=0.690) between the 2 groups. The null allele in the CYP2C19 (rs4244285) [odds ratio (OR)=5.317, 95% confidence interval (CI) 1.542–26.428, P=0.001] and CYP2C19 (rs4986893) (OR=4.295, 95%CI 1.312–17.517, P=0.013) is one of the causes of CR in patients with ACS in China.ConclusionsThe CYP2C19 polymorphism (rs4244285 and rs4986893) is the correlative factor of CR in patients with ACS in China. It was found that the null allele in the CYP2C19 polymorphism was related to the higher CR risk. According to the key role of CYP2C19 in the clopidogrel activation and the evaluated role of CYP2C19 in this study, further studies should be carried out to formulate therapeutic alternative methods for CR in patients with ACS.

A Pharmacogenetic Study of CYP2C19 in Acute Coronary Syndrome Patients of Colombian Origin Reveals New Polymorphisms Potentially Related to Clopidogrel Therapy

“…Our study determined platelet function using the INNOVANCE PFA-200 system (Siemens Healthcare, Germany) which assesses P2Y12-receptor blockades in patients undergoing therapy with P2Y12-receptor antagonists [ 47 ]. Despite some reports indicating a positive correlation between the CT value, HTPR, and MACE frequency [ 13 , 20 , 48 , 49 ], our findings failed to associate the molecular genotype and phenotype of HPR. This result can be attributed to several factors; (a) low frequency of LOF alleles (b) absence of patients with the homozygous genotype for LOF alleles (c) high frequency CYP2C19 *1/*1 with CT suggestive of HPR (d) potential overestimation of patients HPR (technical limitation of PFA-200); (e) involvement of new intronic and/or promoter variants and (f) heterogeneity of response to clopidogrel due to genes not evaluated in this study [ 5 , 50 ].…”

“…It is administered as an inactive prodrug that requires hepatic conversion by cytochrome P450 (CYP) enzymes, mainly 2C19 to produce an active metabolite [ 6 ]. CYP2C19 polymorphisms are related to the anti-platelet effects of clopidogrel [ 4 , 7 , 13 , 24 ]. To the best of our knowledge, this study is the first to assess the variants of the promoter region, the intronic and coding region of CYP2C19 through sequencing in a group of Colombian patients with ACS and determines the association with platelet reactivity.…”

“…In addition to these clinical factors, genetic polymorphisms implicated in the pharmacokinetics and pharmacodynamics of clopidogrel are considered determinants in the response to anti-aggregation therapy, and heritability appears to be responsible for over 70% of interindividual variability [ 6 , 7 , 11 ]. To date, association studies between genetic variants, cardiovascular events, HPR and LPR have focused on polymorphisms on PON1 (p.Q192R), ABCB1 (C.3435C>T) polymorphisms, and particularly the CYP2C19 gene [ 12 , 13 , 14 , 15 ]. CYP2C19, an enzyme of the cytochrome P450 (CYP450) superfamily, is considered the key enzyme related to the bioactivation of clopidogrel through the two-step oxidative process that leads to the formation of 2-oxo-clopidogrel and the active metabolite clopi-H4 [ 16 , 17 ].…”

ABCB1 polymorphism in clopidogrel-treated Montenegrin patients

“…Although no significant difference could be observed between carriers and noncarriers of specific alleles or genotypes in terms of clopidogrel efficacy and safety, it should be noted that the number of patients included in this study is relatively small, that the patients were not on monotherapy with clopidogrel but rather treated with other drugs with potential for both pharmacokinetics and pharmacodynamics interactions with clopidogrel, as well as that other already confirmed genetic factors [ 4 ] were not taken into account during the analysis. Thus, the absence of correlation between ABCB1 genotypes and indicators of efficacy and safety of clopidogrel in this study should be apprehended conditionally, although it conforms well to conclusions of several similar studies [ 31 , 32 , 33 , 34 , 35 ]. Namely, previously published larger and better-controlled studies, which have observed higher risk of clopidogrel resistance [ 36 , 37 ] and higher risk of major cardiovascular adverse events [ 38 ] in carriers of different variant ABCB1 alleles, warrant further investigation of the role of ABCB1 genetic polymorphisms not only in Montenegrins but also in other populations, where clopidogrel remains one of the most frequently prescribed antiplatelet drugs.…”

Distribution of CYP2C19, ABCB1 and PON1 polymorphisms in Chinese Han, Hui, Uygur and Kazak patients with coronary atherosclerotic heart disease

“…ABCB1 variability analyses of Xiaofang Tang et al (Tang et al., 2013) in Chinese people after PCI demonstrated 35.8%, 46.0% and 18.2% of CC, CT and TT distribution frequencies, which correlated well with the distribution analyses of Chinese Han and Hui in our study. Another research in patients with ACS also revealed identical distribution frequencies of 36.0% CC, 48.0% CT and 16.0% TT with Chinese Han and Hui in the present study (Su et al., 2019). Reports involving the ABCB1 polymorphisms in Uygur and Kazak groups were lacking.…”