Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance.
Arachidonic acid metabolism
Aspirin resistance
Clopidogrel activation
Clopidogrel resistance
Epigenomic characteristics
Genomic characteristics
Journal
BMC medical genomics
ISSN: 1755-8794
Titre abrégé: BMC Med Genomics
Pays: England
ID NLM: 101319628
Informations de publication
Date de publication:
20 Jun 2024
20 Jun 2024
Historique:
received:
30
04
2024
accepted:
14
06
2024
medline:
21
6
2024
pubmed:
21
6
2024
entrez:
20
6
2024
Statut:
epublish
Résumé
Mediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks. We enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors. The logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r = 0.291, R This study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors. URL: https://www. gov ; Unique identifier: NCT03823274.
Sections du résumé
BACKGROUND
BACKGROUND
Mediators, genomic and epigenomic characteristics involving in metabolism of arachidonic acid by cyclooxygenase (COX) and lipoxygenase (ALOX) and hepatic activation of clopidogrel have been individually suggested as factors associated with resistance against aspirin and clopidogrel. The present multi-center prospective cohort study evaluated whether the mediators, genomic and epigenomic characteristics participating in arachidonic acid metabolism and clopidogrel activation could be factors that improve the prediction of the aspirin and clopidogrel resistance in addition to cardiovascular risks.
METHODS
METHODS
We enrolled 988 patients with transient ischemic attack and ischemic stroke who were evaluated for a recurrence of ischemic stroke to confirm clinical resistance, and measured aspirin (ARU) and P2Y12 reaction units (PRU) using VerifyNow to assess laboratory resistance 12 weeks after aspirin and clopidogrel administration. We investigated whether mediators, genotypes, and promoter methylation of genes involved in COX and ALOX metabolisms and clopidogrel activation could synergistically improve the prediction of ischemic stroke recurrence and the ARU and PRU levels by integrating to the established cardiovascular risk factors.
RESULTS
RESULTS
The logistic model to predict the recurrence used thromboxane A synthase 1 (TXAS1, rs41708) A/A genotype and ALOX12 promoter methylation as independent variables, and, improved sensitivity of recurrence prediction from 3.4% before to 13.8% after adding the mediators, genomic and epigenomic variables to the cardiovascular risks. The linear model we used to predict the ARU level included leukotriene B4, COX2 (rs20417) C/G and thromboxane A2 receptor (rs1131882) A/A genotypes with the addition of COX1 and ALOX15 promoter methylations as variables. The linear PRU prediction model included G/A and prostaglandin I receptor (rs4987262) G/A genotypes, COX2 and TXAS1 promoter methylation, as well as cytochrome P450 2C19*2 (rs4244285) A/A, G/A, and *3 (rs4986893) A/A genotypes as variables. The linear models for predicting ARU (r = 0.291, R
CONCLUSIONS
CONCLUSIONS
This study demonstrates that different mediators, genomic and epigenomic characteristics of arachidonic acid metabolism and clopidogrel activation synergistically improved the prediction of the aspirin and clopidogrel resistance together with the cardiovascular risk factors.
TRIAL REGISTRATION
BACKGROUND
URL: https://www.
CLINICALTRIALS
RESULTS
gov ; Unique identifier: NCT03823274.
Identifiants
pubmed: 38902747
doi: 10.1186/s12920-024-01936-1
pii: 10.1186/s12920-024-01936-1
doi:
Substances chimiques
Clopidogrel
A74586SNO7
Aspirin
R16CO5Y76E
Platelet Aggregation Inhibitors
0
Banques de données
ClinicalTrials.gov
['NCT03823274']
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
166Subventions
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Organisme : Yuhan Corporation, South Korea
ID : YMC037
Informations de copyright
© 2024. The Author(s).
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