Abstract :- Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is the most commonly used regimen for the secondary prevention of ischemic events in patients with acute coronary syndromes. However, substantial inter-individual variation in response to clopidogrel has been documented, resulting in sub-optimal therapy in some patients and an increased risk of recurrent events. Previous studies indicate that a significant portion of this variation is heritable and a number of genetic variants such as CYP2C19*2 have been found to influence clopidogrel response. However, a substantial amount of the genetic heritability remains unaccounted for. In this study, we conducted the first genome-wide association study of circulating clopidogrel active metabolite levels in 513 healthy participants of the Pharmacogenomics of Antiplatelet Intervention (PAPI) study in order to more directly measure clopidogrel pharmacokinetics. Consistent with previous investigations, we observed that the CYP2C19 locus was the strongest genetic determinant of clopidogrel active metabolite formation (P = 9.5×10^-15). In addition, we identified novel genome-wide significant signals on chromosome 3 (rs187941554, P = 3.3×10^-11), chromosome 17 (rs80343429, P = 1.3×10^-8), and chromosome 19 (rs142890248), as well as 6 additional loci that showed suggestive evidence of association (P ≤1×10^-6).While further investigation is warranted to validate the findings in this study, the analysis of non- traditional measures of clopidogrel response, such as clopidogrel active metabolite concentration, holds promise for further elucidating the clopidogrel metabolic pathway, contributing to improved anti-platelet drug development, and ultimately leading to better patient care in the future.

Keywords: Dual antiplatelet therapy, acute coronary syndromes, clopidogrel pharmacokinetics