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Title

Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

Authors
Verma, Shefali Setia
Bergmeijer, Thomas O
Gong, Li
Lewis, Joshua P
Mitchell, Braxton D
Alexopoulos, Dimitrios
Aradi, Daniel
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Collaboration
Published in Clinical pharmacology and therapeutics. 2020, vol. 108, no. 5, p. 1067-1077
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.
Keywords AgedBlood Platelets/drug effects/metabolismCardiovascular Diseases/blood/genetics/mortality/prevention & controlClopidogrel/adverse effects/therapeutic useCoronary Artery Disease/mortality/therapyCytochrome P-450 CYP2C19/genetics/metabolismFemaleGenome-Wide Association StudyHumansMaleMiddle AgedPercutaneous Coronary Intervention/adverse effects/mortalityPharmacogeneticsPharmacogenomic VariantsPlatelet Aggregation Inhibitors/adverse effects/therapeutic usePolymorphism, Single NucleotideRisk AssessmentRisk FactorsTreatment Outcome
Identifiers
PMID: 32472697
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Article (Published version) (960 Kb) - public document Free access
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Research group Geneva Platelet Group (13)
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VERMA, Shefali Setia et al. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium. In: Clinical Pharmacology and Therapeutics, 2020, vol. 108, n° 5, p. 1067-1077. doi: 10.1002/cpt.1911 https://archive-ouverte.unige.ch/unige:155381

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Deposited on : 2021-10-13

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