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Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.

Publication ,  Journal Article
Lewis, JP; Backman, JD; Reny, J-L; Bergmeijer, TO; Mitchell, BD; Ritchie, MD; Déry, J-P; Pakyz, RE; Gong, L; Ryan, K; Kim, E-Y; Aradi, D ...
Published in: Eur Heart J Cardiovasc Pharmacother
July 1, 2020

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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Published In

Eur Heart J Cardiovasc Pharmacother

DOI

EISSN

2055-6845

Publication Date

July 1, 2020

Volume

6

Issue

4

Start / End Page

203 / 210

Location

England

Related Subject Headings

  • Treatment Outcome
  • Stroke
  • Stents
  • Risk Factors
  • Risk Assessment
  • Predictive Value of Tests
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Platelet Aggregation
  • Pharmacogenomic Variants
 

Citation

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Lewis, J. P., Backman, J. D., Reny, J.-L., Bergmeijer, T. O., Mitchell, B. D., Ritchie, M. D., … ICPC Investigators, . (2020). Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients. Eur Heart J Cardiovasc Pharmacother, 6(4), 203–210. https://doi.org/10.1093/ehjcvp/pvz045
Lewis, Joshua P., Joshua D. Backman, Jean-Luc Reny, Thomas O. Bergmeijer, Braxton D. Mitchell, Marylyn D. Ritchie, Jean-Pierre Déry, et al. “Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.Eur Heart J Cardiovasc Pharmacother 6, no. 4 (July 1, 2020): 203–10. https://doi.org/10.1093/ehjcvp/pvz045.
Lewis JP, Backman JD, Reny J-L, Bergmeijer TO, Mitchell BD, Ritchie MD, et al. Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients. Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(4):203–10.
Lewis, Joshua P., et al. “Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients.Eur Heart J Cardiovasc Pharmacother, vol. 6, no. 4, July 2020, pp. 203–10. Pubmed, doi:10.1093/ehjcvp/pvz045.
Lewis JP, Backman JD, Reny J-L, Bergmeijer TO, Mitchell BD, Ritchie MD, Déry J-P, Pakyz RE, Gong L, Ryan K, Kim E-Y, Aradi D, Fernandez-Cadenas I, Lee MTM, Whaley RM, Montaner J, Gensini GF, Cleator JH, Chang K, Holmvang L, Hochholzer W, Roden DM, Winter S, Altman RB, Alexopoulos D, Kim H-S, Gawaz M, Bliden KP, Valgimigli M, Marcucci R, Campo G, Schaeffeler E, Dridi NP, Wen M-S, Shin JG, Fontana P, Giusti B, Geisler T, Kubo M, Trenk D, Siller-Matula JM, Ten Berg JM, Gurbel PA, Schwab M, Klein TE, Shuldiner AR, ICPC Investigators. Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients. Eur Heart J Cardiovasc Pharmacother. 2020 Jul 1;6(4):203–210.
Journal cover image

Published In

Eur Heart J Cardiovasc Pharmacother

DOI

EISSN

2055-6845

Publication Date

July 1, 2020

Volume

6

Issue

4

Start / End Page

203 / 210

Location

England

Related Subject Headings

  • Treatment Outcome
  • Stroke
  • Stents
  • Risk Factors
  • Risk Assessment
  • Predictive Value of Tests
  • Polymorphism, Single Nucleotide
  • Platelet Aggregation Inhibitors
  • Platelet Aggregation
  • Pharmacogenomic Variants