A genetic polymorphism in P2RY1 impacts response to clopidogrel in cats with hypertrophic cardiomyopathy

Yu Ueda,Eric S. Ontiveros,Michael H. Court,Joshua A. Stern,Maureen S. Oldach,Karen M. Vernau,Nghi Nguyen,Samantha L. Kovacs,Ronald H. L. Li

doi:10.1038/s41598-021-91372-3

Yu Ueda, Eric S. Ontiveros + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-91372-3

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Abstract

Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. It is frequently used in cats with hypertrophic cardiomyopathy (HCM) to prevent thromboembolic complications. However, significant interpatient variability of the response to clopidogrel therapy has been suspected. In this study, we assessed the impact of single nucleotide polymorphisms (SNPs) within ADP receptor (P2RY1, P2RY12) and cytochrome P450 isoenzyme (CYP2C41) genes on platelet inhibition by clopidogrel administration in cats with HCM. Forty-nine cats completed the study, and blood samples were obtained before and after clopidogrel therapy to assess the degree of platelet inhibition based on flow cytometry and whole blood platelet aggregometry. Plasma concentrations of clopidogrel metabolites were measured after the last dose of clopidogrel. Whole blood platelet aggregometry revealed a significant reduction of platelet inhibition by clopidogrel in cats with the P2RY1:A236G and the P2RY12:V34I variants. The association with the P2RY1:A236G variant and clopidogrel resistance remained significant after adjustment for multiple comparisons. This study demonstrated that a genetic polymorphism in the P2RY1 gene altered response to clopidogrel therapy and suggests that clinicians may consider alternative or additional thromboprophylactic therapy in cats with the P2RY1:A236G variant.

Highlights

Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor
We hypothesized that genetic polymorphisms in the genes encoding the feline platelet adenosine diphosphate (ADP) receptors, P2RY1:A236G and P2RY12:V34I and the feline cytochrome P450 2C enzyme, CYP2C41:H231R, are common and responsible for clopidogrel resistance in cats with hypertrophic cardiomyopathy (HCM)
phosphorylation of vasodilator-stimulated phosphoprotein (P-VASP) expression was significantly lower in P GE1 and ADP-treated platelets (MFI 2924, IQR 2165–3631) than PGE1-treated platelets (P < 0.0001) but higher than ADP-treated platelets (P < 0.0001) (Fig. 2a). These results indicate that activation of the P2Y12 receptor by ADP inhibits the adenyl cyclase-cyclic AMP pathway leading to lower P-VASP in platelets

Summary

Introduction

Clopidogrel is converted to its active metabolite by cytochrome P450 isoenzymes and irreversibly inhibits platelet activation by antagonizing the adenosine-diphosphate (ADP) receptor. The aforementioned clinical trial in cats showed frequent recurrence of ATE despite clopidogrel therapy and underscores the potential for variable response to this drug in clinical p atients[10] In addition to these findings, recent studies reported interindividual variability of platelet inhibition by clopidogrel assessed by platelet aggregometry and flow cytometry in cats with and without hypertrophic cardiomyopathy (HCM)[14,15]. We hypothesized that genetic polymorphisms in the genes encoding the feline platelet ADP receptors, P2RY1:A236G and P2RY12:V34I and the feline cytochrome P450 2C enzyme, CYP2C41:H231R, are common and responsible for clopidogrel resistance in cats with HCM To test this hypothesis, the frequencies of the non-synonymous SNPs in client-owned cats with HCM were determined. The results were compared in HCM cats with and without the nonsynonymous SNPs identified in the targeted genes

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