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Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel:
Shefali Setia Verma1, Thomas O Bergmeijer2, Li Gong3
1Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Insights
Genetic factors influence clopidogrel response. While CYP2C19*2 is a major determinant of platelet reactivity, other genes like SCOS5P1, CDC42BPA, and CTRAC1 may impact clinical outcomes in specific patient groups.
Area of Science:
- Pharmacogenomics
- Cardiovascular Genetics
- Clinical Pharmacology
Background:
- Antiplatelet therapy response, particularly to clopidogrel, exhibits significant inter-individual variability.
- Poor clopidogrel response is linked to adverse clinical events, highlighting the need to understand its determinants.
- While CYP2C19 loss-of-function alleles are known contributors, they explain only a fraction of response variability.
Purpose of the Study:
- To identify additional genetic factors influencing clopidogrel pharmacodynamics and clinical response.
- To investigate genetic associations with adenosine diphosphate-induced platelet reactivity and major adverse cardiovascular and cerebrovascular events.
Main Methods:
- A genomewide association study (GWAS) was conducted on 2,750 individuals of European ancestry.
- Platelet reactivity and clinical endpoints (cardiovascular death, myocardial infarction, stroke) were used as outcome measures.
- Statistical analyses included correction for the known CYP2C19*2 variant.
Main Results:
- The CYP2C19*2 allele was confirmed as the strongest genetic determinant of clopidogrel's effect on platelet reactivity (P=1.67e-33).
- No other single nucleotide polymorphism reached genomewide significance for platelet reactivity after accounting for CYP2C19*2.
- In specific subgroups (coronary artery disease, PCI, ACS), novel associations with SCOS5P1, CDC42BPA, and CTRAC1 were identified for clinical outcomes.
Conclusions:
- CYP2C19*2 is the primary genetic predictor of clopidogrel's impact on platelet function.
- Novel genetic associations suggest potential roles for SCOS5P1, CDC42BPA, and CTRAC1 in clopidogrel's clinical efficacy within specific cardiovascular contexts.
Abstract:
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.