The genetic basis of platelet responsiveness to clopidogrel

2011 ◽  
Vol 106 (08) ◽  
pp. 203-210 ◽  
Author(s):  
Paul Fefer ◽  
Shlomi Matetzky
Keyword(s):  
Coronary Artery Disease ◽  
Genetic Polymorphisms ◽  
Active Metabolite ◽  
Genetic Basis ◽  
Genetic Factors ◽  
Platelet Inhibition ◽  
Clinical Implications ◽  
Wide Range ◽  
Metabolite Generation ◽  
Artery Disease

SummaryClopidogrel reduces ischaemic complications in a wide range of patients with coronary artery disease. However, there is much inter-individual variation in clopidogrel-induced platelet inhibition, and a substantial proportion of patients will exhibit non-responsiveness to clopidogrel. Multiple studies have demonstrated an association between the presence of genetic polymorphisms associated with suboptimal clopidogrel-active metabolite generation, decreased platelet responsiveness, and adverse clinical outcomes. However, it is not clear to what extent the genetic polymorphisms account for the observed variability in response to clopidogrel. In this review we provide a critical summary of the available evidence linking genetic factors with response to clopidogrel, and discuss the clinical implications of this association.

Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways

2013 ◽  
Vol 110 (12) ◽  
pp. 1223-1231 ◽  
Author(s):  
Dominick J. Angiolillo ◽  
Jose L. Ferreiro ◽  
Joseph A. Jakubowski ◽  
Kenneth J. Winters ◽  
Mark B. Effron ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Active Metabolite ◽  
Platelet Reactivity ◽  
Coronary Intervention ◽  
Platelet Inhibition ◽  
Reactivity Index ◽  
Coronary Syndrome ◽  
Metabolite Generation ◽  
Artery Disease ◽  
The Impact

SummaryClopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

Molecular Evaluation of MicroRNA-146 Gene Variability (rs2910164 C> G) and its Association with Increased Susceptibility to Coronary Artery Disease

MicroRNA ◽  
2020 ◽  
Vol 09 ◽  
Author(s):  
Rashid Mir ◽  
Imadeldin Elfaki ◽  
Chandan k Jha ◽  
Jamsheed Javid ◽  
Suriya Rehman ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genetic Factors ◽  
Mirna Gene ◽  
Amplification Refractory Mutation System ◽  
Coronary Artery Diseases ◽  
Increased Risk ◽  
Inheritance Model ◽  
Artery Disease ◽  
Increased Susceptibility

Aim: Apart from the modifiable risk factors, genetic factors are believed to also influence the outcome of the coronary artery diseases (CAD). Under the genetic factors, miRNA polymorphisms, namely Hsa-miR-146a-5p (rs2910164) have become an important tool to study the mechanism that underlies the pathogenesis of this disease. Therefore, we investigated the association of miR-146a gene variations with susceptibility of coronary artery diseases. Methodology: This study was conducted on 100 CAD patients and 117 matched healthy individuals. Genotyping of the Hsa-miR-146a-5p C>G gene variation was performed by using amplification refractory mutation system PCR method (ARMS-PCR). Results: The distribution of Hsa-miR-146a-5p rs2910164 C>G genotypes observed between patients and controls was significantly different (P=0.048). Moreover, the frequency of G allele (fG) was found to be significantly higher among patients than in controls (0.36 vs. 0.25). Our findings showed that the Hsa-miR-146a-5p C>G variant was associated with an increased risk of CAD in codominant inheritance model CC vs. CG genotype (OR = 1.84, 95 % CI, 1.02-3.31; p=0.040) and (OR = 3.18, 95 % CI, 1.02-9.9; p=0.045) for CC vs. GG genotype in dominant inheritance model. Whereas the G allele significantly increased the risk of coronary artery disease (OR =1,81, 95 % CI, 1.18-2.78; p=0.006) compared to C allele. Taken together, these results demonstrated that miR-146a/rs2910164 is associated with susceptibility to coronary artery disease, providing novel insights into the genetic etiology and underlying biology of coronary artery disease. Conclusion: Our findings indicated that Hsa-miR-146a-5p rs2910164 GG genotype and G allele are associated with an increased susceptibility to Coronary Artery Disease. A larger sample size can be the key to progress in establishing the genetic co-relation of miRNA gene polymorphisms and cardiovascular diseases.

Genetic factors in primary hypertension and coronary artery disease a reappraisal

1962 ◽  
Vol 15 (12) ◽  
pp. 1093-1108 ◽  
Author(s):  
Morton D. Schweitzer ◽  
E.Gurney Clark ◽  
Frances R. Gearing ◽  
George A. Perera
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genetic Factors ◽  
Primary Hypertension ◽  
Artery Disease

scholarly journals Anticoagulation in Patients with Ischaemic Heart Disease and Peripheral Arterial Disease: Clinical Implications of COMPASS Study

2018 ◽  
Vol 13 (2) ◽  
pp. 115 ◽  
Author(s):  
Josep Gradolí ◽  
Verónica Vidal ◽  
Adrian JB Brady ◽  
Lorenzo Facila ◽  
◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Arterial Disease ◽  
Platelet Inhibition ◽  
Clinical Implications ◽  
Peripheral Artery ◽  
Everyday Clinical Practice ◽  
Major Cardiovascular Events ◽  
Novel Oral Anticoagulant ◽  
Artery Disease ◽  
Peripheral Arterial

Patients with established cardiovascular disease may suffer further cardiovascular events, despite receiving optimal medical treatment. Although platelet inhibition plays a central role in the prevention of new events, the use of anticoagulant therapies to reduce events in atheromatous disease has, until recently, been overlooked. The recent Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) study showed an important reduction in cardiovascular events without increasing the risk of fatal and intracranial bleeding when using rivaroxaban, a novel oral anticoagulant, combined with aspirin. This article reviews the available evidence regarding the use of anticoagulant therapies for prevention of cardiovascular events, the results of the COMPASS study and how these results may affect patient management in everyday clinical practice.

P874Role of Genetic Polymorphisms of ion channels in the pathophysiology of coronary microvascular dysfunction and ischemic heart disease: an update

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Pucci ◽  
P Severino ◽  
A D'Amato ◽  
L Netti ◽  
R Scarpati ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Artery Disease ◽  
Heart Disease ◽  
Cardiovascular Risk ◽  
Coronary Artery ◽  
Ion Channels ◽  
Ischemic Heart Disease ◽  
Cardiovascular Risk Factors ◽  
Genetic Polymorphisms ◽  
Artery Disease

Abstract Background Ischemic heart disease (IHD) is classically associated with coronary artery disease (CAD) and conventional cardiovascular risk factors. However, IHD may exhibit in the absence of CAD, because of different pathophysiological mechanisms, such as the presence of specific genetic variants of ion channels, which act mainly in the microcirculation. Recently, we reported the correlation between some single nucleotide polymorphisms (SNPs) of ion channels genes and the presence of IHD, independently from the presence of conventional cardiovascular risk factors. The goal of this study is to confirm the results of the previous study on a bigger population and discover new SNPs of ion channels genes which may be associated with IHD. Methods A prospective, observational, single-center study was conducted on patients candidates for coronary angiography. Patients were divided in three groups: G1, coronary artery disease; G2, microvascular disfunction; G3, normal. Genetic polymorphisms relative to KCNJ11 encoding for the Kir6.1 and Kir6.2 subunits of K-ATP channels and KCNE1 encoding for the MinK subunit of IKs channels were analyzed. Results 603 consecutive patients (G1: 409; G2:76; G3:118) were enrolled. Genetic analysis for the three groups showed a statistically significant difference for the SNP S38G of KCNE1 (p=0.001) and for the variants rs5215, rs5218, rs5219 of KCNJ11 (p<0.0001), as well as comparing G1-G3 (S38G p=0.006; rs5215, rs5218 and rs5219 p<0.0001). Regarding G1-G2 we confirmed differences only for the variants rs5215 (p<0.0001), rs5218 (p=0.005) and rs5219 (p=0.024), while regarding G2-G3 we found differences for the variants S38G, rs5215 e rs5219 (p<0.0001). A multivariate analysis was performed and highlighted that the SNP rs5215_GG of KCNJ11 may represent an IHD independent protective factor (p<0.0001; OR: 0.036; 95.0% CI: 0.018–0.069). Conclusion These results confirm the importance of genetic susceptibility and the role of SNPs of ion channels genes in the determinism of IHD, independently from the conventional cardiovascular risk factors. Moreover, these results may represent a future perspective for a genic therapy for IHD.

Sign in / Sign up

Export Citation Format

Share Document