Key result
CYP2C19*2 variant linked to ~137% greater risk of HTPR in clopidogrel-treated CAD patients.
Why the study?
Clopidogrel resistance has been associated with interindividual variability in treatment response across ethnicities leading to adverse coronary events, prompting evaluation of genetic and clinical factors in South Indian CAD patients.
Do genetic variants (CYP2C19, PON1) and clinical factors predict high on-treatment platelet reactivity in South Indian CAD patients treated with clopidogrel?
Observational (n=197)
No
Do genetic variants (CYP2C19, PON1) and clinical factors predict high on-treatment platelet reactivity in South Indian CAD patients treated with clopidogrel?
Odds Ratio: 2.37 (95% CI 1.16–4.84)
p-value: p=0.02
In South Indian CAD patients, CYP2C19 loss-of-function alleles and clinical factors like BMI and diabetes significantly increase the risk of clopidogrel resistance, highlighting the potential for personalized antiplatelet therapy.
May support genotype-informed clopidogrel use in South Indian CAD; leaves open whether testing improves outcomes in trials.
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.
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Bharath et al. (2025) conducted an observational in Coronary artery disease (CAD) (n=197). CYP2C19*2 variant vs. Wild-type genotype was evaluated on High on-treatment platelet reactivity (HTPR) (OR 2.37, 95% CI 1.16-4.84, p=0.02). The CYP2C19*2 variant was associated with a significantly increased risk of high on-treatment platelet reactivity (OR 2.37) in South Indian patients with coronary artery disease treated with clopidogrel.
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