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Objectives: CYP2C19*2 loss-of-function (LoF) allele is associated with reduced antiplatelet effect of clopidogrel. This study was aimed to assess the association between CYP2C19*2 LoF alleles and platelet reactivity in healthy Malaysian volunteers.
Methods: Genotypes of 23 healthy human volunteers were assessed for wild-type CYP2C19*1 and CYP2C19*2 LoF alleles, using polymerase chain amplification. Polymorphism screening was performed by direct sequencing. The volunteers were classified into 2 groups on the basis of CYP2C19 genotype, namely Good Metabolizer (GM, CYP2C19*1/*1, n=10) and Reduced Metabolizer (RM, CYP2C19*1/*2, n=8 and CYP2C19 *2/*2, n=5). They received a 300-mg oral loading dose (LD) of clopidogrel and platelet reactivity was assessed at 4 hours post-LD using VerifyNow-P2Y12 assay. The results were reported in P2Y12 Reaction Units (PRU), mean PRU change and percent inhibition (%). Platelet function measurements according to genotype were analyzed using independent t-test or one-way ANOVA using SPSS, version 17.0 software (SPSS. Inc., Chicago, Illinois).
Results: Mean BASE platelet reactivity for GM and RM were 299.00±32.60 and 323.31±45.38 PRU, respectively (p=0.167). When treated with 300-mg oral LD, RM had significantly higher mean PRU than GM (226.31±68.20 vs. 105.70±63.51 PRU, p<0.001). Mean PRU changes and percent inhibition were the lowest in RM group (97.00±85.88 vs. 193.30±60.34 PRU, p=0.007; 29.38±21.67 vs. 64.80±19.50 %, p=0.001). Gene-dose trend, observed as mean PRU, differed significantly according to number of CYP2C19*2 allele presence (105.70±63.51 in*1/*1 vs. 199.13±66.59 in *1/*2 vs. 269.80±48.49 PRU in *2/*2; overall p<0.001). The same trend was observed for percent inhibition and mean PRU changes.
Conclusions: The CYP2C19*2 LoF allele is associated with a marked decrease in platelet responsiveness to clopidogrel in healthy Malaysian volunteers particularly in CYP2C19*2/*2 carriers. As the number of reduced alleles is important, the observed effect warrants a further investigation in a clinical setting as it may be an important contributor to clopidogrel resistance.