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

Publication ,  Journal Article
Verma, SS; Bergmeijer, TO; Gong, L; Reny, J-L; Lewis, JP; Mitchell, BD; Alexopoulos, D; Aradi, D; Altman, RB; Bliden, K; Bradford, Y; Campo, G ...
Published in: Clin Pharmacol Ther
November 2020

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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Published In

Clin Pharmacol Ther

DOI

EISSN

1532-6535

Publication Date

November 2020

Volume

108

Issue

5

Start / End Page

1067 / 1077

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Risk Factors
  • Risk Assessment
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Pharmacology & Pharmacy
  • Pharmacogenomic Variants
  • Pharmacogenetics
  • Percutaneous Coronary Intervention
  • Middle Aged
 

Citation

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Verma, S. S., Bergmeijer, T. O., Gong, L., Reny, J.-L., Lewis, J. P., Mitchell, B. D., … ICPC Investigators, . (2020). 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, 108(5), 1067–1077. https://doi.org/10.1002/cpt.1911
Verma, Shefali Setia, Thomas O. Bergmeijer, Li Gong, Jean-Luc Reny, Joshua P. Lewis, Braxton D. Mitchell, Dimitrios Alexopoulos, et al. “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 108, no. 5 (November 2020): 1067–77. https://doi.org/10.1002/cpt.1911.
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.Clin Pharmacol Ther, vol. 108, no. 5, Nov. 2020, pp. 1067–77. Pubmed, doi:10.1002/cpt.1911.
Verma SS, Bergmeijer TO, Gong L, Reny J-L, Lewis JP, Mitchell BD, Alexopoulos D, Aradi D, Altman RB, Bliden K, Bradford Y, Campo G, Chang K, Cleator JH, Déry J-P, Dridi NP, Fernandez-Cadenas I, Fontana P, Gawaz M, Geisler T, Gensini GF, Giusti B, Gurbel PA, Hochholzer W, Holmvang L, Kim E-Y, Kim H-S, Marcucci R, Montaner J, Backman JD, Pakyz RE, Roden DM, Schaeffeler E, Schwab M, Shin JG, Siller-Matula JM, Ten Berg JM, Trenk D, Valgimigli M, Wallace J, Wen M-S, Kubo M, Lee MTM, Whaley R, Winter S, Klein TE, Shuldiner AR, Ritchie MD, ICPC Investigators. 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.
Journal cover image

Published In

Clin Pharmacol Ther

DOI

EISSN

1532-6535

Publication Date

November 2020

Volume

108

Issue

5

Start / End Page

1067 / 1077

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Risk Factors
  • Risk Assessment
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Pharmacology & Pharmacy
  • Pharmacogenomic Variants
  • Pharmacogenetics
  • Percutaneous Coronary Intervention
  • Middle Aged