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Effects of cytochrome P450 2C19 and paraoxonase 1 polymorphisms on antiplatelet response to clopidogrel therapy in patients with coronary artery disease.

Tresukosol D, Suktitipat B, Hunnangkul S, Kamkaew R, Poldee S, Tassaneetrithep B, Likidlilid A - PLoS ONE (2014)

Bottom Line: Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results.The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders.The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.

ABSTRACT
Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75-325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65-5.26; p<0.001) and 11.26 (95%CI, 2.47-51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70-1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98 × 10(-6)). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

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Interaction among polymorphisms in CYP2C19*2, *3 and PON1 Q192R and the effects on ADP-induced platelet aggregation.A) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*2 genotype; B) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*3 genotype; C) Effects of CYP2C19*2 on platelet aggregation stratified by CYP2C19*3 genotype
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pone-0110188-g001: Interaction among polymorphisms in CYP2C19*2, *3 and PON1 Q192R and the effects on ADP-induced platelet aggregation.A) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*2 genotype; B) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*3 genotype; C) Effects of CYP2C19*2 on platelet aggregation stratified by CYP2C19*3 genotype

Mentions: Since both CYP2C19 and PON1 involve in activation of clopidogrel prodrug as suggested by Bouman et al. [20], the interaction effects between CYP2C19 (*2, *3) and PON1 (Q192R) on ADP-induced platelet aggregation were investigated. After stratification by CYP2C19*2 (Figure 1A) and *3 genotypes (Figure 1B), the effects of PON1 (Q192R) polymorphism on ADP-induced platelet aggregation were not modified by neither CYP2C19*2 nor CYP2C19*3 allele. Cordell's test for epistatic interaction showed no statistically significant interaction between CYP2C19*2 or *3 with PON1 Q192R polymorphisms (pint = 0.21 and 0.91, respectively). Similarly, CYP2C19*3 did not modify the effects of CYP2C19*2 on ADP-induced platelet aggregation (pint = 0.65, Figure 1C). To examine the extent of linkage disequilibrium (LD) in these study samples, standardized LD coefficient (D′) and correlation coefficient (r) were calculated for all pairs of polymorphisms. Table 6 shows the LD matrix generated using D′ and r. No evidence of LD was observed among these three polymorphisms (D′ and r<0.5).


Effects of cytochrome P450 2C19 and paraoxonase 1 polymorphisms on antiplatelet response to clopidogrel therapy in patients with coronary artery disease.

Tresukosol D, Suktitipat B, Hunnangkul S, Kamkaew R, Poldee S, Tassaneetrithep B, Likidlilid A - PLoS ONE (2014)

Interaction among polymorphisms in CYP2C19*2, *3 and PON1 Q192R and the effects on ADP-induced platelet aggregation.A) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*2 genotype; B) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*3 genotype; C) Effects of CYP2C19*2 on platelet aggregation stratified by CYP2C19*3 genotype
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199712&req=5

pone-0110188-g001: Interaction among polymorphisms in CYP2C19*2, *3 and PON1 Q192R and the effects on ADP-induced platelet aggregation.A) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*2 genotype; B) Effects of PON1 Q192R polymorphism on platelet aggregation stratified by CYP2C19*3 genotype; C) Effects of CYP2C19*2 on platelet aggregation stratified by CYP2C19*3 genotype
Mentions: Since both CYP2C19 and PON1 involve in activation of clopidogrel prodrug as suggested by Bouman et al. [20], the interaction effects between CYP2C19 (*2, *3) and PON1 (Q192R) on ADP-induced platelet aggregation were investigated. After stratification by CYP2C19*2 (Figure 1A) and *3 genotypes (Figure 1B), the effects of PON1 (Q192R) polymorphism on ADP-induced platelet aggregation were not modified by neither CYP2C19*2 nor CYP2C19*3 allele. Cordell's test for epistatic interaction showed no statistically significant interaction between CYP2C19*2 or *3 with PON1 Q192R polymorphisms (pint = 0.21 and 0.91, respectively). Similarly, CYP2C19*3 did not modify the effects of CYP2C19*2 on ADP-induced platelet aggregation (pint = 0.65, Figure 1C). To examine the extent of linkage disequilibrium (LD) in these study samples, standardized LD coefficient (D′) and correlation coefficient (r) were calculated for all pairs of polymorphisms. Table 6 shows the LD matrix generated using D′ and r. No evidence of LD was observed among these three polymorphisms (D′ and r<0.5).

Bottom Line: Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results.The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders.The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Siriraj, Bangkoknoi, Bangkok, Thailand.

ABSTRACT
Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75-325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65-5.26; p<0.001) and 11.26 (95%CI, 2.47-51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70-1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98 × 10(-6)). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

Show MeSH
Related in: MedlinePlus