背景:调解员,涉及环氧合酶(COX)和脂氧合酶(ALOX)代谢花生四烯酸和氯吡格雷肝脏激活的基因组和表观基因组特征被认为是与阿司匹林和氯吡格雷抵抗相关的因素.当前的多中心前瞻性队列研究评估了调解员是否,除了心血管风险外,参与花生四烯酸代谢和氯吡格雷激活的基因组和表观基因组特征可能是改善阿司匹林和氯吡格雷抵抗预测的因素.
方法:我们招募了988例短暂性脑缺血发作和缺血性卒中患者,这些患者被评估为缺血性卒中的复发,以确认临床耐药性。在服用阿司匹林和氯吡格雷12周后,使用VerifyNow评估实验室抵抗,并测量阿司匹林(ARU)和P2Y12反应单位(PRU)。我们调查了调解员,基因型,与COX和ALOX代谢和氯吡格雷激活有关的基因的启动子甲基化可以通过整合已确定的心血管危险因素来协同改善缺血性卒中复发的预测以及ARU和PRU水平。
结果:预测复发的逻辑模型使用血栓素A合酶1(TXAS1,rs41708)A/A基因型和ALOX12启动子甲基化作为独立变量,and,将复发预测的敏感性从添加介体前的3.4%提高到添加介体后的13.8%,心血管风险的基因组和表观基因组变量。我们用于预测ARU水平的线性模型包括白三烯B4,COX2(rs20417)C/G和血栓烷A2受体(rs1131882)A/A基因型,并添加了COX1和ALOX15启动子甲基化作为变量。线性PRU预测模型包括G/A和前列腺素I受体(rs4987262)G/A基因型,COX2和TXAS1启动子甲基化,以及细胞色素P4502C19*2(rs4244285)A/A,G/A,和*3(rs4986893)A/A基因型作为变量。预测ARU(r=0.291,R2=0.033,p<0.01)和PRU(r=0.503,R2=0.210,p<0.001)水平的线性模型在增加基因组和表观基因组变量后改善了心血管风险的预测性能。
结论:这项研究表明,不同的介体,花生四烯酸代谢和氯吡格雷激活的基因组和表观基因组特征协同改善了阿司匹林和氯吡格雷抵抗以及心血管危险因素的预测。
背景:URL:https://www。
结果:gov;唯一标识符:NCT03823274。
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: 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: 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, R2 = 0.033, p < 0.01) and PRU (r = 0.503, R2 = 0.210, p < 0.001) levels had improved prediction performance after adding the genomic and epigenomic variables to the cardiovascular risks.
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.
BACKGROUND: URL: https://www.
RESULTS: gov ; Unique identifier: NCT03823274.