The pharmacogenetic control of antiplatelet response: candidate genes and<i>CYP2C19</i>

Yao, Yang; Lewis, Joshua P.; Hulot, Jean‐Sébastien; Scott, Stuart A.

doi:10.1517/17425255.2015.1068757

Cited by 25 publications

(24 citation statements)

References 200 publications

(226 reference statements)

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“…6 The CYP2C19 enzyme is encoded by a highly polymorphic gene and CYP2C19 single nucleotide polymorphisms have been identified as significantly and consistently associated with variability in clopidogrel response. [6][7][8][9] The *2 variant allele is the most common CYP2C19 loss-offunction allele, translating to decreased CYP2C19 enzyme activity, with an estimated prevalence of 29% to 35% in Asians and 15% in Caucasians and Africans. 7 Non-carriers of the *2 allele (homozygous *1/*1) are classified as extensive metabolizers (EMs), carriers of one *2 allele (heterozygous *1/*2) as intermediate metabolizers (IMs) and carriers of two *2 alleles (homozygous *2/*2) as poor metabolizers (PMs) of clopidogrel.…”

Section: Introductionmentioning

confidence: 99%

“…The strongest association was reported in patients with acute coronary syndrome undergoing PCI with stent implantation, where *2 allele carriers had an increased risk of stent thrombosis. 8,9 In-stent restenosis (ISR) is another well-documented complication of PCI. 10 Although the rate of ISR decreased significantly with the use of DES compared to balloon angioplasty and BMS, it still persisted as a limiting factor for the long-term benefit of PCI, with an approximate rate of 10% in non-complex lesions.…”

Section: Introductionmentioning

confidence: 99%

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CYP2C19*2 Allele Carrier Status and Coronary In-stent Restenosis: Is There an Association?

Wirth¹,

Zahra²,

Xuereb³

et al. 2018

Journal of Exploratory Research in Pharmacology

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Background and objective: The CYP2C19*2 allele is associated with reduced clopidogrel bioactivation, increasing the risk of complications after percutaneous coronary intervention (PCI), particularly stent thrombosis. Recently published data suggests that CYP2C19*2 allele carriers have a higher risk for in-stent restenosis (ISR) after endovascular treatment. Very few studies have investigated the relationship between CYP2C19*2 and coronary ISR, with no significant association reported. The objective of this study was to assess the relationship between CYP2C19*2 allele carrier status and coronary ISR. Methods: Patients with previous PCI with stenting and who were scheduled for elective PCI after coronary angiogram were recruited from the cardiac catheterization suite over a 12-month period. The angiography report of each patient was perused to identify patients requiring PCI due to ISR. For patients with angiography-confirmed ISR, date of previous PCI to the restenosed stent was noted. CYP2C19*2 genotyping was undertaken using a TaqMan ® Drug Metabolism assay. The association between CYP2C19*2 allele carrier status and incidence of coronary ISR within 1 year was assessed using Fisher's exact test (p < 0.05 significance) and by calculating the odds ratio (OR) with a 95% confidence interval (CI). Results: Of the 82 patients with previous PCI, 29 (35.4%) had angiography-confirmed ISR (12 carriers, 17 noncarriers of CYP2C19*2). In 13 (44.8%) of these patients, the restenosed stent was deployed within 1 year and the patients were on clopidogrel therapy at the time of repeat PCI (8 carriers, 5 non-carriers of CYP2C19*2). The association between CYP2C19*2 allele carrier status and ISR within 1 year was not statistically significant (Fisher's exact p = 0.067; OR: 4.80, 95% CI: 0.98-23.54, p = 0.053). Conclusions: Despite a higher proportion of CYP2C19*2 allele carriers exhibiting ISR within 1 year compared to non-carriers, the association was not statistically significant. This result may be attributed to the small sample size, and larger prospective studies are recommended to further assess this association.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CYP2C19*2 Allele Carrier Status and Coronary In-stent Restenosis: Is There an Association?

Wirth¹,

Zahra²,

Xuereb³

et al. 2018

Journal of Exploratory Research in Pharmacology

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“…Clopidogrel is a pro-drug that is activated in the liver by several cytochrome P450 enzymes (CYPs) to the active metabolite, 2-oxo-clopidogrel, which inhibits platelet aggregation by binding irreversibly to purinergic receptor P2Y, G-protein coupled, 12 (P2Y12 receptor) (Sangkuhl et al, 2010 ; Fitzgerald and Fitzgerald, 2013 ; Yang et al, 2015 ). It can also be hydrolyzed, independent of CYP activity, by hepatic esterases, mainly carboxylesterase 1 (CES1), which generates the inactive carboxylic acid metabolite (CAM) (Beitelshees et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of miR-26a-5p and miR-15b-5p Exosomal Expression Associated with Clopidogrel-Induced Hepatotoxicity in HepG2 Cells

et al. 2017

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Clopidogrel is an essential antiplatelet drug used to prevent thrombosis complications associated with atherosclerosis. However, hepatotoxicity is a potential adverse effect related to clopidogrel therapy. Exosome-derived miRNAs may be useful for improved monitoring of drug response and hepatotoxicity risk. In the present study, the expression of several exosomal miRNAs (miR-26a-5p, miR-145-5p, miR-15b-5p, and miR-4701-3p) and cell-derived mRNA targets (PLOD2, SENP5, EIF4G2, HMGA2, STRADB, and TLK1) were evaluated in HepG2 cells treated with clopidogrel (6.25, 12.5, 25, 50, and 100 μM) for 24 and 48 h. Then, clopidogrel cytotoxicity was evaluated by analyzing DNA fragmentation and the cell cycle profile using flow cytometry. Differential expression of exosome-derived miRNAs and cell-derived mRNAs was analyzed by RT-qPCR. Exposure of HepG2 cells to high concentrations of clopidogrel (50 and 100 μM) for 24 h caused significant DNA fragmentation (17.6 and 44.4%, respectively; p < 0.05) and 48 h (26.8 and 48.9%, respectively; p < 0.05), indicating cellular toxicity. Upregulation of miR-26a-5p and downregulation of miR-15b-5p was observed in cells exposed to 100 μM clopidogrel for 24 and 48 h. The miR-26a-5p target mRNAs HMGA2, EIF4G2, STRADB, and SENP5 were downregulated in HepG2 cells following exposure to cytotoxic concentrations of clopidogrel (50 and 100 μM) for 24 h, and HMGA2 levels remained low after 48 h of treatment. TLK1, a target of miR-15b-5p, was downregulated by 50 and 100 μM clopidogrel at 24 h. In conclusion, our results suggest that exposure to high concentrations of clopidogrel modulates the expression of exosomal miR-26a-5p and miR-15b-5p and their target mRNAs in HepG2 cells. Dysregulation of these miRNAs maybe modulate the regulatory pathways involved in clopidogrel-induced liver injury.

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“…As a major metabolizing enzyme, CYP2C19 is involved in catalyzing the bioactivation of many commonly used drugs in humans [ 1 ]. Clopidogrel is a thienopyridine derivative that has antiplatelet effects through the inhibition of platelet adenosine receptors (e.g., P2Y12) after bioactivation by the cytochrome P450 metabolic system [ 2 , 3 ]. Genetic factors have been extensively studied in clopidogrel-treated patients with acute coronary syndrome (ACS) [ 4 – 6 ].…”

Section: Introductionmentioning

confidence: 99%

Distribution of CYP2C19 polymorphisms in Mongolian and Han nationals and the choice of specific antiplatelet drugs

Wang

Hu-ping

2017

Int J Clin Pharm

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Background Individualized medication reviews may improve our understanding of the distribution of CYP2C19 polymorphisms in ethnic populations. Objective To evaluate differences in CYP2C19 gene polymorphisms between Mongolian and Han nationals and determine the effect of adjustments of antiplatelet treatments according to the genetic profile in patients undergoing percutaneous coronary intervention (PCI). Setting Prospective, observational, single-center study. Methods 397 patients diagnosed with acute coronary syndrome were enrolled. Additionally, 186 patients undergoing PCI were given different treatments according to their CYP2C19 genotypes. Patients with the genotype of an extensive metabolizers (EMs; *1/*1) were co-administered aspirin 100 mg/day and clopidogrel 75 mg/day, following a loading dose of 300 mg; intermediate metabolizers (IMs; e.g., *1/*2 and *1/*3) and poor metabolizers (PMs; e.g., *2/*2 and *2/*3) were administered a loading dose of 180 mg ticagrelor, followed by a maintenance dose of 90 mg twice a day. Results In Mongolians, 60.79% of patients were EMs, which was significantly higher than that in Han nationals (P = 0.002). In Han individuals, 62.14% of patients were IMs and PMs, which was significantly higher than that in Mongolians (P < 0.05). Three patients died, and the frequency of adverse events during follow-up was significantly higher in patients given conventional treatment than in patients given tailored treatment (P = 0.039). However, differences in metabolism subtypes did not affect the incidence of adverse reactions. Conclusions There were differences in CYP2C19 polymorphisms between Mongolians and Hans. Effective, safe therapy was achieved by tailoring antiplatelet drug therapy based on genotype.

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The pharmacogenetic control of antiplatelet response: candidate genes andCYP2C19

Cited by 25 publications

References 200 publications

CYP2C19*2 Allele Carrier Status and Coronary In-stent Restenosis: Is There an Association?

CYP2C19*2 Allele Carrier Status and Coronary In-stent Restenosis: Is There an Association?

Modulation of miR-26a-5p and miR-15b-5p Exosomal Expression Associated with Clopidogrel-Induced Hepatotoxicity in HepG2 Cells

Distribution of CYP2C19 polymorphisms in Mongolian and Han nationals and the choice of specific antiplatelet drugs

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