Association of genetic polymorphism of CYP2C19, P2Y12 and response to Clopidogrel in healthy participants.

ABSTRACT Clopidogrel, a Thienopyridine derivative, irreversibly inhibits platelet aggregation by antagonizing the action of adenosine diphosphate (ADP) on purinergic (P2Y12) receptor. It is used in acute coronary syndromes, ischemic stroke and also recently indicated for atrial fibrillation. Clopidogrel is a prodrug requiring biotransformation mainly by the hepatic Cytochrome P450 enzyme 2C19 (CYP2C19) to generate an active metabolite. Studies done in the west have shown a large variability in the clopidogrel response. It has been reported that the variant forms of CYP2C19 gene are associated with poor responsiveness to the drug. There is no data available in the Indian population and hence the present study was envisaged with the objective of evaluating the association of polymorphisms of CYP2C19 and P2Y12 with inhibition of platelet aggregation (IPA) to a single oral dose of 300 mg Clopidogrel in adult Indian healthy participants. Healthy adults (n=25) of either sex were enrolled after obtaining written informed consent and administered single dose of 300 mg clopidogrel. Blood samples (9 ml) were collected for platelet aggregation tests at the baseline (pre-dose), 4 hours post-dose. Additionally, 5 ml blood was collected from each participant for genotyping. Baseline and four hours post-dose of platelet aggregation and genotype of CYP2C19 and P2Y12 were carried out using standardized laboratory methods. The difference in the maximal platelet aggregation (MPA) between baseline and four hours post-dose was considered as delta-MPA (DMPA) and percent change of MPA at four hours from baseline was considered as inhibition of platelet aggregation (IPA). Those with an IPA of < 30% were considered as poor responders. Inferential statistics was applied to find out significant difference of these parameters between various groups of genetic polymorphisms. Wide range of inter individual variations to Clopidogrel response was noted in the 25 healthy volunteers. Mean (SD) of MPA (%) at baseline and 4 hours post-dose were 75.8 (6.5) and 54 (17) respectively. Similarly, mean (SD) of DMPA (%) and IPA (%) were 21.8 (16) and 29 (21.5) respectively. A total of 13/25 (52%) were found to be poor responders to clopidogrel. A wild genotype (*1/*1) of CYP2C19 was observed in 15 (60%), 8 (32%) had *1/*2 and 2 (8%) had *2/*2 mutant genotypes. Although statistically not significant (p = 0.3624), a trend was observed in having decreased inhibition values (both MPA and IPA) as we proceed from wild genotype (*1/*1) to the mutant genotypes in this order: *1/*2 and *2/*2. Similarly, in P2Y12, a wild haplotype (H1/H1) was present in 20 (80%) and 5 (20%) individuals had H1/H2. No significant difference or trend was observed in DMPA or IPA values between H1 and H2 haplotypes of P2Y12. We found a trend of decrease in the inhibition of platelet aggregation with CYP2C19 genotypes and an increase in the same with the H2 haplotype of P2Y12 following clopidogrel in Indian healthy adults. Assessment of genetic polymorphisms of the same may aid in personalizing the therapy with clopidogrel. KEYWORDS: Clopidogrel, CYP2C19, P2Y12, polymorphism. REFERENCES Gupta R et al. (2008). Epidemiology and Causation of coronary heart disease and stroke in India. Heart, 94:16-26. Peters D et al. (2001). Raising the sights: Better Health Systems for India’s Poor. In WHO case study: India. Washington DC: The World Bank. WHO Collaborative programme. (2008-2009). Clinical Management Guidelines for Coronary Artery Disease for National Programme for Prevention and Control of Diabetes, Cardiovascular Disease and Stroke. Chandigarh. Valentin Fuster, M. P. (1992, January 30). Mechanisms of disease ‐ the pathogenesis of coronary‐artery disease and the acute coronary syndromes. 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