P2RY12 gene polymorphisms and effect of clopidogrel on platelet aggregation (original) (raw)
Related papers
Thrombosis Research, 2005
Introduction: Clopidogrel inhibits the ADP subtype P2Y 12 receptor. Recently, polymorphisms of this receptor have been associated with different degrees of platelet aggregation in healthy volunteers and have been suggested to modulate clopidogrel response. However, the role of gene sequence variations of the P2Y 12 receptor in patients treated with clopidogrel has not yet been assessed. Materials and methods: The T744C polymorphism of the P2Y 12 receptor gene was assessed in 119 patients: 36 undergoing coronary stenting receiving a 300 mg loading dose (Group A) and 83 on long-term clopidogrel (75 mg/day) treatment (Group B). Patients were divided into 2 subgroups according to the presence or absence of the C allele: carriers (CT heterozygotes and CC homozygotes) and non-carriers (TT homozygotes). Platelet aggregation, assessed by light transmittance aggregometry following ADP, collagen, TRAP and epinephrine stimuli, and platelet activation (GP IIb/IIIa activation and P-selectin expression), assessed by whole blood flow 0049-3848/$ -see front matter D Thrombosis Research (2005) 116, 491 -497
Thrombosis Research, 2007
Background: Variability in platelet response to clopidogrel and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. Recently, the T744C polymorphism of the P2Y12 receptor gene has been associated with enhanced platelet aggregation in healthy volunteers, suggesting a possible mechanism for modulation of clopidogrel response. Aim of this study: To assess whether the clopidogrel response may be influenced by the T744C P2Y12 gene polymorphism in patients with non ST elevation acute coronary syndrome (NSTE ACS). Methods: 597 NSTE ACS patients were included in our study and were divided into 3 groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples. Clopidogrel response was assessed by posttreatment ADP 10 μmol/L-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression (PS). Clopidogrel resistance was Thrombosis Research (2007) 120, [893][894][895][896][897][898][899] defined by persistence of High Post-treatment Platelet Reactivity (HPPR = ADP-Ag N 70%). Results: Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameter profiles was observed within patients having the same genotype, for ADP-Ag (p = 0.39), PRI VASP (p = 0.97) and PS (p = 0.62). The genotype frequencies of the T744C polymorphism of the P2Y12 gene were similar in responders and non responders defining by HPPR (p = 0.75). Conclusion: Our study did not show any influence of the T744C polymorphism of the P2Y12 receptor gene on clopidogrel response assessed by ADP-Ag, PRI VASP or Pselectin expression in NSTE ACS patients.
Blood Coagulation & Fibrinolysis, 2013
Platelets have a central role in the pathophysiology of thrombosis. Adenosine diphosphate (ADP) plays a pivotal role as an agonist of platelet activation. Genetic polymorphisms of the P2Y12 ADP receptor might influence the activation of this receptor by ADP or the response of patients to platelet inhibitors. The present study was conducted on a total number of 80 participants, 40 patients were diagnosed with acute coronary syndrome and 40 sex and aged-matched healthy volunteers were included as controls. Platelet aggregation was assessed (before and 1 week after clopidogrel administration) and genotyping of the T744C genetic polymorphism of P2Y12 receptor gene was carried out using the restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. Platelet aggregation of the patients had a range of 54-183% before clopidogrel administration and had a range of 4-113% after its administration. Genotyping of the candidate gene revealed that 72.5% of the patients had a wild allele (TT), whereas 27.5% had a C allele (heterozygous CT, homozygous CC). On the contrary, 97.5% of controls had a wild allele (TT), whereas 2.5% had a C allele (heterozygous CT, homozygous CC). Our study elicited an association between the T744C polymorphism of the P2Y12 ADP receptor gene and platelet reactivity. Carrying the C allele at this position is associated with an increased platelet activation response to ADP.
Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 2016
This study was designed to investigate the effect of clopidogrel-related gene polymorphisms on platelet reactivity and clinical outcome in Chinese Han patients. Three hundred and thirty-six percutaneous coronary intervention - treated patients were recruited and followed for 1 year. Blood samples were collected from all patients for DNA genotyping. The platelet reactivity unit was measured by the VerifyNow technique. The CYP2C19*2, CYP2C19*3, CYP2C19*17, ATP-binding cassette subfamily B member 1, ITGB3, CYP2C9*3, CYP2B6*9, and P2Y12 alleles were assessed. The clinical endpoints were related to previous heart disease history (11.90% vs. 28.57%, P = 0.017), stroke (12.24% vs. 16.67%, P = 0.039), and diabetes (27.55% vs. 52.38%, P = 0.047). High on-treatment platelet reactivity (HTPR) was frequent in advanced age (P = 0.019), male gender (P = 0.016), hypertension (P = 0.033), and chronic renal failure (P = 0.040). There were more endpoints in the CYP2C19*2 and P2Y12 mutant carriers (76...
Platelets, 2012
Aspirin and Clopidogrel are used in prophylaxis of patients undergoing percutaneous coronary intervention and long-term prevention of cardiovascular and cerebrovascular events. Clopidogrel resistance has been attributed to P2Y 1 and P2Y 12 adenosine diphosphate (ADP) receptor polymorphisms. This study enrolled 100 patients of coronary artery disease (CAD) who were on the maintenance dose of clopidogrel (75 mg OD) with or without aspirin. In addition, 10 received loading dose (300 mg) prior to percutaneous coronary intervention. Relevant clinical and drug history were elicited. ADP-induced platelet aggregation study and PCR-RFLP for P2Y 1 (1622A4G) and P2Y 12 (i-T744C) polymorphisms were performed. Two groups of controls were used for defining cutoff for platelet aggregation response. Follow-up data, wherever available was recorded. The most common pattern of aggregation response was disaggregation, either complete (46.4%) or partial (53.6%). A frequency of 13% clopidogrel non-responders and 19% semi-responders was found. All the cases were H1/H1 haplotype for P2Y 12 gene polymorphism and 28 (29.2%) patients carried P2Y 1 1622A4G (21(21.9%) AG and 7(7.3%) GG) gene polymorphism, the frequency being greater in clopidogrel responders compared to semi/non-responders but difference was not statistically significant. There was no statistically significant difference between responders and semi/non-responders in terms of the history of risk factor for CAD, concurrent atorvastatin use or past history of an acute vascular event. On follow up, the two patients who developed myocardial infarction/acute coronary syndromes (MI/ACS) were clopidogrel semi-and non-responder, respectively. Variability in clopidogrel response with 13% non-responders and 19% semi-responders was seen in this study with adverse outcome (MI/ACS) on follow up seen in two patients. Hence, poor response to clopidogrel may be related to increased likelihood of adverse long-term coronary event that may benefit from additional or alternative antiplatelet therapy. Clopidogrel resistance was not associated with ADP receptor P2Y 1 and P2Y 12 gene polymorphisms. Hence, it is postulated that clopidogrel resistance in CAD patients is multifactorial and not caused by single-gene polymorphisms.
Thrombosis Research, 2012
Introduction: Information regarding any possible additional effect of genetic variants other than CYP2C19*2 on platelet reactivity in patients undergoing percutaneous coronary intervention (PCI), while on dual antiplatelet therapy, is sparse. Materials and Methods: Genotyping for CYP2C19*2, CYP2C19*17, CYP2C9*3, CYP2B6*5, ABCB1 and P2RY12 (c.-217 + 2739 T N C) variants was performed in 146 consecutive PCI patients receiving clopidogrel. Platelet reactivity was assessed by the Verify Now P2Y12 point-of-care assay and high on-treatment platelet reactivity (HTPR) was defined as a Platelet Reactivity Unit (PRU) ≥ 235. Results: We identified 65(44.5%) patients with HTPR and 38(26%) carriers of at least one CYP2C19*2 allele, which had higher platelet reactivity compared to non-carriers [least square (LS) mean difference 44.5, 95%CI 15.8-77.3, p = 0.003]. In the entire study population, the presence of at least one CYP2C19*2 or P2RY12 allelic variant was independently associated with HTPR (OR = 3.02, 95%CI 1.16-7.86, p = 0.023 and OR = 3.11, 95%CI 1.03-9.39, p = 0.05 respectively). In CYP2C19*2 non-carriers, carriers of at least one CYP2B6*5 allelic variant had higher platelet reactivity compared to the remainders (LS mean difference 35.6, 95%CI 3.7-67.6, p = 0.03) and the presence of at least one CYP2B6*5 or P2RY12 allelic variant was independently associated with HTPR (OR = 3.26, 95%CI 1.08-9.86, p = 0.04 and OR = 4.27, 95%CI 1.11-16.4, p = 0.04 respectively). Conclusions: Apart from the CYP2C19*2, other genetic variants involved in clopidogrel metabolism and action like CYP2B6*5 and P2RY12 seem to have an important association with HTPR.