Molecular genomic and epigenomic characteristics related to aspirin and clopidogrel resistance

• Published in: BMC medical genomics Vol. 17; no. 1; pp. 166 - 12
• Main Authors: Kim, Jei, Shin, Byoung-Soo, Kim, Dae-Hyun, Shin, Dong-Ick, Ahn, Seong Hwan, Kim, Jae Guk, Ryu, Su Hyun, Moon, Hye Rin, Kang, Hyun Goo, Jeong, Hyeseon, Yum, Kyu Sun, Chae, Hee-Yun, Kim, Do-Hyung, Kang, Keunsoo, Kim, Jeeyeon
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20-06-2024; BioMed Central; BMC
• Subjects: Aged; Arachidonic acid; Arachidonic acid metabolism; Aspirin; Aspirin - pharmacology; Aspirin - therapeutic use; Aspirin resistance; Cardiovascular diseases; Clopidogrel; Clopidogrel - pharmacology; Clopidogrel - therapeutic use; Clopidogrel activation; Clopidogrel resistance; Cyclooxygenase-1; Cyclooxygenase-2; Cytochrome P450; Diseases; DNA methylation; DNA Methylation - drug effects; Dosage and administration; Drug Resistance - genetics; Epigenetics; Epigenomic characteristics; Epigenomics; Female; Genes; Genomic characteristics; Genomics; Genotypes; Hospitals; Humans; Ischemia; Laboratories; Leukotriene B4; Life sciences; Lipoxygenase; Male; Metabolism; Metabolites; Middle Aged; Pharmacodynamics; Pharmacokinetics; Platelet Aggregation Inhibitors - pharmacology; Platelet Aggregation Inhibitors - therapeutic use; Prediction models; Prevention; Prospective Studies; Relapse; Risk factors; Stroke; Stroke (Disease); Thromboxane A2; Transcription activation; Transient ischemic attack; South Korea; United States > US; Aspirin resistance; Arachidonic acid metabolism; Genomic characteristics; Epigenomic characteristics; Clopidogrel activation; Clopidogrel resistance
• ISSN: 1755-8794; 1755-8794
• DOI: 10.1186/s12920-024-01936-1

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
 = 0.033, p < 0.01) and PRU (r = 0.503, R
 = 0.210, p < 0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks.
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.