Integrative pharmacogenomics analysis predicts the platelet response in clopidogrel treated coronary artery disease (CAD) patients of South India.

Clopidogrel resistance/high on-treatment platelet reactivity (HTPR) has been associated with interindividual variability in the clopidogrel treatment response in different ethnicities leading to adverse coronary events. The current study evaluated the effect of genetics and clinical factors on platelet inhibition in clopidogrel-treated South Indian CAD patients. We genotyped 15 genetic polymorphisms in the genes associated with the pharmacokinetics and pharmacodynamics of clopidogrel. We observed a high prevalence of the poor metabolizer CYP2C19*2 (34%) variant and CYP2C19-based high-risk metabolizer phenotype such intermediate and poor metabolizer (IM + PM) with 68.5% in CAD patients. The platelet function test revealed that 31% of the CAD cases were HTPR phenotypes (VASP PRI > 50%). The CYP2C19*2 [OR 2.37 (95% CI 1.16-4.84), p = 0.02], high risk CYP2C19 metabolizer phenotypes [OR 1.72 (95% CI 1.08-2.77), p = 0.02] showed increased risk of HTPR. However, PON1 (rs662) favoured better response to clopidogrel [OR 0.50 (95% CI 0.32-0.80), p = 0.004]. Similarily, the multivariate linear regression showed that the CYP2C19*2 (rs4244285) and P2RY12 (rs6809699) and clinical factors (BMI, type II diabetes, and biguanides usage) were associated with high platelet reactivity, while PON1 (rs662) contributed to better platelet inhibition by clopidogrel. The current study revealed predictive integrated pharmacogenomics tool to identify the genetic and clinical factors that determine the clopidogrel response for personalized therapeutic management of CAD patients of South Indian ethnicity.