Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Biomarkers predictive of late cardiogenic shock development in patients with suspected ST-elevation myocardial infarction

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Ultrasound-assisted thrombolysis for acute intermediate-high-risk pulmonary embolism

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Joshua P Lewis
  • Joshua D Backman
  • Jean-Luc Reny
  • Thomas O Bergmeijer
  • Braxton D Mitchell
  • Marylyn D Ritchie
  • Jean-Pierre Déry
  • Ruth E Pakyz
  • Li Gong
  • Kathleen Ryan
  • Eun-Young Kim
  • Daniel Aradi
  • Israel Fernandez-Cadenas
  • Ming Ta Michael Lee
  • Ryan M Whaley
  • Joan Montaner
  • Gian Franco Gensini
  • John H Cleator
  • Kiyuk Chang
  • Lene Holmvang
  • Willibald Hochholzer
  • Dan M Roden
  • Stefan Winter
  • Russ Altman
  • Dimitrios Alexopoulos
  • Ho-Sook Kim
  • Meinrad Gawaz
  • Kevin Bliden
  • Marco Valgimigli
  • Rossella Marcucci
  • Gianluca Campo
  • Elke Schaeffeler
  • Nadia P Dridi
  • Ming-Shien Wen
  • Jae Gook Shin
  • Pierre Fontana
  • Betti Giusti
  • Tobias Geisler
  • Michiaki Kubo
  • Dietmar Trenk
  • Jolanta M Siller-Matula
  • Jurriën M Ten Berg
  • Paul A Gurbel
  • Matthias Schwab
  • Teri E Klein
  • Alan R Shuldiner
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftEuropean heart journal. Cardiovascular pharmacotherapy
Vol/bind6
Udgave nummer4
Sider (fra-til)203-210
Antal sider8
ISSN2055-6837
DOI
StatusUdgivet - 2020

ID: 59123249