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Updated: Jan 19, 2026
Human Height-a Polygenic Trait
Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in
Joshua P Lewis1, Joshua D Backman1, Jean-Luc Reny2,3
1Department of Medicine and Program for Personalized and Genomic Medicine, University of Maryland, 670 W. Baltimore St., Baltimore, MD 21201, USA.
Insights
Genetic variations influence how well clopidogrel works. A new score combining multiple gene variants predicts cardiovascular events, paving the way for personalized medicine in clopidogrel treatment.
Area of Science:
- Pharmacogenomics
- Cardiovascular Medicine
- Genetics
Background:
- Clopidogrel is a key medication for preventing atherothrombotic events.
- Individual responses to clopidogrel vary due to genetic factors, but their clinical utility in predicting major adverse cardiovascular events (CVEs) is debated.
Purpose of the Study:
- To assess the impact of 31 candidate gene polymorphisms on clopidogrel's antiplatelet effect.
- To determine if these genetic variants predict major adverse cardiovascular events (CVEs) in clopidogrel-treated patients.
Main Methods:
- Analyzed 31 gene polymorphisms in 3391 coronary artery disease patients treated with clopidogrel.
- Assessed adenosine diphosphate (ADP)-stimulated platelet reactivity.
- Tested polymorphism influence on CVEs in 2134 patients with available clinical data.
Main Results:
- Several variants (e.g., CYP2C19*2, CES1 G143E) significantly affected on-treatment platelet reactivity.
- No single variant predicted CVEs.
- A pharmacogenomic polygenic response score (PgxRS) showed that patients with more risk alleles had higher rates of CVEs and cardiovascular death.
Conclusions:
- Multiple polymorphisms influence clopidogrel response.
- The PgxRS is a valuable predictor of cardiovascular outcomes.
- Further research into genetic determinants and polygenic models can advance precision medicine strategies for clopidogrel therapy.
Aims:
Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial.
Methods And Results:
We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10-54; CES1 G143E, P = 1.3 × 10-16; CYP2C19*17, P = 9.5 × 10-10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10-4; CYP2B6 516 G > T, P = 1.0 × 10-3; CYP2C9*2, P = 1.2 × 10-3; and CYP2C9*3, P = 1.5 × 10-3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14-2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35-14.27, P = 0.01) compared to patients who carried six or fewer of these alleles.
Conclusion:
Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.
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