Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel

Wp, Zhong; H, Wu; Chen, Jy; Xx, Li; Hua, Lin; Zhang, B; Zw, Zhang; Ma, Dong; Sun, Shuhan; Hp, Li; Lp, Mai; Gd, He; Wang, XP; Hp, Lei; Hk, Zhou; Tang, Lan; Liu, Stanley K.; Sl, Zhong

doi:10.1002/cpt.589

Cited by 27 publications

(24 citation statements)

References 48 publications

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“…The authors observed that newly identified N6AMT1 rs2254638 polymorphism was associated with clopidogrel response and H4 concentration in both pharmacokinetic replication cohort and function replication cohort. Consistent with these findings, results from an independent cohort of CHD patients suggested the rs2254638 polymorphism as a risk factor for major adverse cardiac events (MACE) after PCI (Zhong et al, 2017 ). Zhong's research provides further evidence for the influence of genetic variants in the pharmacokinetics pathway on clopidogrel response.…”

Section: Introductionmentioning

confidence: 70%

“…Both CYP2C19 * 2 and CYP2C19 * 3 lead to truncated proteins by producing early-stop codons (Cui et al, 2015 ). Recently, a GWAS suggested that N6AMT1 rs2254638 polymorphism was associated with P2Y12 reaction unit (PRU) and H4 concentration ex vivo in CAD patients with clopidogrel therapy (Zhong et al, 2017 ). Furthermore, the polymorphism was identified to exert a marginal risk effect for MACE in an independent patient cohort (Zhong et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study, Zhong et al identified an association of the intronic single nucleotide polymorphism (SNP) rs2254638 in N-6-adenine-specific DNA methyltransferase 1 ( N6AMT1 ) with clopidogrel response in patients undergoing PCI (Zhong et al, 2017 ). Specially, based on genome wide association study (GWAS) in 115 coronary heart disease (CHD) patients underwent PCI, the rs2254638 variant affected both the plasma concentration of H4 and on-treatment platelet activity assessed by VerifyNow assay.…”

Section: Introductionmentioning

confidence: 99%

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Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

Zhang

et al. 2018

Front. Pharmacol.

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Dual antiplatelet treatment with aspirin and clopidogrel is the standard therapy for patients undergoing percutaneous coronary intervention (PCI). However, a portion of patients suffer from clopidogrel resistance (CR) and consequently with recurrence of cardiovascular events. Genetic factors such as loss-of-function variants of CYP2C19 contribute a lot to CR. Recently, the N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) rs2254638 polymorphism is reported to be associated with clopidogrel response. To validate the association between N6AMT1 rs2254638 polymorphism and clopidogrel response, 435 Chinese CAD patients receiving aspirin and clopidogrel were recruited. N6AMT1 rs2254638 and CYP2C19*2/*3 polymorphisms were genotyped. Platelet reaction index (PRI) was measured by VASP-phosphorylation assay after treated with a 300 mg loading dose (LD) clopidogrel or 75 mg daily maintenance dose (MD) clopidogrel for at least 5 days. There was a significant difference in PRI between LD cohort and MD cohort. Carriers of CYP2C19*2 allele showed significantly increased PRI in the entire cohort and in respective of the MD and LD cohorts (p < 0.001, p = 0.003, p < 0.001, respectively). However, carriers of CYP2C19*3 allele exhibited significantly higher PRI only in the entire cohort and LD cohort (p = 0.023, p = 0.023 respectively). PRI value was significantly higher in CYP2C19 PM genotyped patients as compared with those carrying the IM genotypes and EM genotype (p < 0.001). Besides, carriers of the rs2254638 C allele showed significantly higher PRI in entire cohort and in the LD cohort (p = 0.023, p = 0.008, respectively). When the patients were grouped into clopidogrel resistance (CR) and non-clopidogrel resistance (non-CR) groups, CYP2C19*2 was associated with increased risk of CR in the entire cohort, the LD cohort and the MD cohort (p < 0.001, p < 0.001, and p = 0.019, respectively). Carriers of the rs2254638 C allele also showed increased risk of CR in the entire cohort and the LD cohort (p = 0.024, and p = 0.028, respectively). N6AMT1 rs2254638 remained as a strong predictor for CR (TC vs. TT: OR = 1.880, 95% CI = 1.099–3.216,p = 0.021; CC vs. TT: OR = 1.930, 95% CI = 1.056-3.527, p = 0.032; TC + CC vs. TT: OR = 1.846, 95%CI = 1.126–3.026, p = 0.015) after adjustment for confounding factors. Our study confirmed the influence of CYP2C19*2 and rs2254638 polymorphisms on clopidogrel resistance in Chinese CAD patients. Both CYP2C19*2 and N6AMT1 rs2254638 polymorphism may serve as independent biomarkers to predict CR.

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Section: Introductionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

Zhang

et al. 2018

Front. Pharmacol.

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“…In this study, no single SNP reached genomewide significance (P value < 7.11e−8) for platelet reactivity measured by VerifyNow (PRU cutoff > 208), although 125 SNPs in 25 genes showed suggestive evidence of association (P value < 1.0e−4). 40 Of those 125 SNPs, 27 were also associated with clopidogrel active metabolite levels (P value < 0.01), of which 23 were within the HELLS-CYP2C18-CYP2C19 cluster, being in strong LD with one another and with CYP2C19*2. Multiple regression analysis showed that a combination of CYP2C19*2, rs2254638 in N6AMT1, and rs2487032 in ABCA1 could explain 28.2% of antiplatelet response (10.9%, 14.8%, and 2.5% per SNP, respectively), which increased to 37.7% when clinical factors (use of calcium channel blockers and sex) were added to the model.…”

Section: Discussionmentioning

confidence: 99%

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

Verma

Bergmeijer

Gong

et al. 2020

Clin Pharma and Therapeutics

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Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using

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“…The main severe and relatively common side effect of antiplatelet therapy is a higher risk of hemorrhage, for example, gastrointestinal bleeding and intracranial and intracerebral hemorrhage (12,13). Another limitation affecting the efficiency of many antiplatelet drugs is genetic differences in the ability to metabolize prodrugs, such as clopidogrel, acquired anaphylaxis (heparin and aspirin) and drug resistance (aspirin) (14,15). Thus, there is a need to develop novel platelet inhibitors with better efficacy and safety.…”

Section: Introductionmentioning

confidence: 99%

Antiplatelet Activity of Tussilagone via Inhibition of the GPVI Downstream Signaling Pathway in Platelets

et al. 2020

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Tussilagone is a sesquiterpenoid extracted from Tussilago farfara and is used as an oriental medicine for asthma and bronchitis. Although previous studies have shown that tussilagone has an inhibitory effect on platelet aggregation, no studies have been performed to investigate its precise effect on platelets, and the underlying mechanism remains unclear. In the present study, we showed that tussilagone inhibited platelet aggregation induced by collagen, thrombin and ADP, as well as platelet release induced by collagen and thrombin, in mice. Tussilagone decreased P-selectin expression and αIIbβ3 activation (JON/A binding) in activated platelets, which indicated that tussilagone inhibited platelet activation. Moreover, tussilagone suppressed platelet spreading on fibrinogen and clot retraction. The levels of phosphorylated Syk, PLCγ2, Akt, GSK3β, and MAPK (ERK1/2 and P38) and molecules associated with GPVI downstream signaling were downregulated in the presence of tussilagone. In addition, tussilagone prolonged the occlusion time in a mouse model of FeCl 3-induced carotid artery thrombosis and had no effect on mouse tail bleeding time. These results indicate that tussilagone inhibits platelet function in vitro and in vivo and that the underlying mechanism involves the Syk/PLCγ2-PKC/MAPK and PI3K-Akt-GSK3β signaling pathways downstream of GPVI. This research suggests that tussilagone is a potential candidate antiplatelet drug for the prevention of thrombosis.

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Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel

Cited by 27 publications

References 48 publications

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

Association of N6AMT1 rs2254638 Polymorphism With Clopidogrel Response in Chinese Patients With Coronary Artery Disease

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

Antiplatelet Activity of Tussilagone via Inhibition of the GPVI Downstream Signaling Pathway in Platelets

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