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

Clin Pharmacol Ther. 2020 Nov;108(5):1067-1077. doi: 10.1002/cpt.1911. Epub 2020 Jul 9.


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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Blood Platelets / drug effects*
  • Blood Platelets / metabolism
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / prevention & control*
  • Clopidogrel / adverse effects
  • Clopidogrel / therapeutic use*
  • Coronary Artery Disease / mortality
  • Coronary Artery Disease / therapy*
  • Cytochrome P-450 CYP2C19 / genetics*
  • Cytochrome P-450 CYP2C19 / metabolism
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Percutaneous Coronary Intervention* / adverse effects
  • Percutaneous Coronary Intervention* / mortality
  • Pharmacogenetics
  • Pharmacogenomic Variants*
  • Platelet Aggregation Inhibitors / adverse effects
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Polymorphism, Single Nucleotide*
  • Risk Assessment
  • Risk Factors
  • Treatment Outcome


  • Platelet Aggregation Inhibitors
  • Clopidogrel
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19