Abstract
There has been a wide range of inter-individual variations in platelet responses to clopidogrel. The variations in response to clopidogrel can be driven by genetic polymorphisms involved in the pathway of absorption, distribution, metabolism, excretion, and the target receptor P2Y12. A set of genetic variants known for causing variations in clopidogrel responses was selected, which included CYP2C19*2, *3, *17, CYP2B6*4, *6, *9, CYP3A4*18, CYP3A5*3, MDR1 2677G > T/A, 3435C > T, and P2Y12 H2 (742T > C). The simultaneous detection of these 10 variants was developed by using a multiplex PCR and single-base extension (MSSE) methodology. The newly developed genotyping test was confirmed by direct DNA sequencing in the representative positive control samples and validated in an extended set of 100 healthy Korean subjects. Genotyping results from the developed MSSE exhibited a perfect concordance with the direct DNA sequencing data and all of variants tested in 100 healthy Korean subjects were in agreement with Hardy-Weinberg equilibrium (p > 0.05). The present molecular diagnostic studies provide an accurate, convenient, and fast genotyping method for the detection of multiple variants. This would be helpful for researchers, as well as clinicians, to use genetic information toward more personalized medicine of clopidogrel and other antiplatelet drugs in the future.
Highlights
Clopidogrel is a member of the thienopyridine class of adenosine diphosphate (ADP) receptor inhibitor, which inhibits platelet aggregation by irreversibly binding to P2Y12 receptor on platelet membrane [1]
The goal of the present study was to develop an accurate, fast and cost-effective genotyping method using multiplex PCR and single-base extension (MSSE) strategy for the detection of a set of multiple variants known for associated with variable clopidogrel responses
Clopidogrel must be bio-transformed into its active metabolite to exert its antiplatelet effects, which is accomplished by hepatic cytochrome P450 isoenzymes, including CYP2C19, CYP2B6, CYP3A4, and CYP3A5 [17,18]
Summary
Clopidogrel is a member of the thienopyridine class of adenosine diphosphate (ADP) receptor inhibitor, which inhibits platelet aggregation by irreversibly binding to P2Y12 receptor on platelet membrane [1]. The response to clopidogrel differs widely from subject to subject, and about 25% of patients treated with standard clopidogrel dose exhibit insufficient inhibition of ADP-induced platelet aggregation [2]. Individuals carrying ABCB1 3435 TT genotypes have exhibited reduced platelet inhibition with increased risk of recurrent ischemic events during anti-platelet drug treatment [4]. In patients with acute coronary syndromes who have undergone percutaneous intervention, nearly half of the individuals having major adverse cardiovascular events were found to carry a genotype associated with increased risk alleles of ABCB1 and CYP2C19 [5], suggesting that the improved prediction of cardiovascular events could be possible when combined with both ABCB1 and CYP2C19 genotypes than the application of individual gene alone. Genetic polymorphisms in the P2Y12 gene have been suggested to contribute to inter-individual variations in clopidogrel response in patients [6]
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