Key result
GWAS confirms CYP2C19*2 predicts platelet reactivity but reveals no novel genetic variants for MACE.
Why the study?
Antiplatelet response to clopidogrel varies widely and CYP2C19 loss-of-function alleles explain only a small part of this variability, motivating identification of other genetic determinants.
Observational (n=2,750)
Yes
Odds Ratio: 1.31 (95% CI 0.87–1.99)
Absolute Event Rate: 5.8% vs 4.2%
p-value: p=0.20
CYP2C19*2 remains central to clopidogrel response prediction; leaves open discovery of variants linked to clinical outcomes.
Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
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Verma et al. (2020) conducted an observational in Patients on clopidogrel therapy for coronary artery disease, PCI, or ACS (n=2,750). CYP2C19*2 loss-of-function allele vs. CYP2C19*2 noncarriers was evaluated on Major adverse cardiovascular events (MACE: cardiovascular death or myocardial infarction) (OR 1.31, 95% CI 0.87-1.99, p=0.20). A genomewide association study confirmed CYP2C19*2 as the strongest predictor of on-treatment platelet reactivity but found no novel genetic variants reaching genomewide significance for clinical cardiovascular outcomes.
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