The Association of Genetic Variants and Non-Genetic Factors with Efficacy of Clopidogrel in the Egyptian Population

Abstract

Aspirin and clopidogrel are the standard of care for patients undergoing ACS and/or PCI. Despite their unambiguous clinical benefit, a considerable number of patients continues to experience MACE. Studies have shown that platelet response to clopidogrel is heterogeneous. Clopidogrel is a prodrug that needs to be converted into active metabolite. ABCB1 is a drug transporter gene, encoding for P-glycoprotein in intestine that exports clopidogrel to circulation. After its absorption, only 15% of clopidogrel undergoes a two-step oxidation by a series of hepatic CYP450 to generate the active metabolite, which irreversibly binds to the ADP P2Y12 receptor and inhibits platelet aggregation. Several lines of evidences suggest that variability in active metabolite generation is the primary explanation for the interindividual variability of clopidogrel response. Studies have shown that polymorphisms in the genes responsible for the metabolism and activation of clopidogrel (e.g.: ABCB1 and CYP2C19) led to a large interindividual variability of clopidogrel response. CYP2C19 catalytic efficiency is mainly affected by the CYP2C19*2 polymorphism in exon 5, which results in a truncated non-functional and CYP2C19*3 in exon 4, which produces a premature stop codon. Conversely, the CYP2C19*17 allele, a regulatory region variant, is associated with increased expression and enzymatic activity. This variability translates into different rates of conversion of clopidogrel to its active compound. In