与氯吡格雷反应相关的DNA甲基化和单核苷酸多态性：急性冠状动脉综合征的全基因组DNA甲基化分析
DNA methylation and single-nucleotide polymorphism associated with clopidogrel response: a whole-genome DNA methylation analysis in acute coronary syndrome.
作者信息
Song Pei-Yuan, Li Mu-Peng, Peng Li-Ming, Chen Xiao-Ping
机构信息
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, China.
出版信息
Res Pract Thromb Haemost. 2023 Feb 24;7(2):100093. doi: 10.1016/j.rpth.2023.100093. eCollection 2023 Feb.
BACKGROUND
Dual antiplatelet therapy with clopidogrel and aspirin is the primary treatment for patients who undergo percutaneous coronary intervention. However, the interindividual difference in clopidogrel response is remarkable, and high on-treatment platelet reactivity (HTPR) can increase the risk of thrombotic events after percutaneous coronary intervention.
OBJECTIVE
We studied novel accessible factors that possibly affect clopidogrel response in DNA methylation.
METHODS
Methylation 850K bead chips were used to detect DNA methylation levels. The platelet reactivity index (PRI) was determined in 330 subjects with acute coronary syndrome (ACS) after administration of clopidogrel 300 mg loading dose or at least 5 days of 75 mg daily maintenance dose.
RESULTS
Overall, 32 discovery samples showed extreme clopidogrel response: 16 with HTPR (PRI > 75%) and 16 with non-HTPR (PRI < 26%). Overall, 61 differential methylation loci (DMLs) were observed between the 2 groups. Most were in the open sea and intergenic regions in the genome. In the validation stage, HTPR showed a lower level of cg06300880 methylation. Carriers of rs34394661 AA genotype, a CpG-single-nucleotide polymorphism at the cg06300880 locus, showed an increased odds for HTPR (overall odds ratio of patients with ACS = 7.31, 95% CI: 1.69-31.59, = .008; non-ST elevation myocardial infarction-ACS: odds ratio = 12.69, 95% CI: 1.68-96.08, = .01) and decreased cg06300880 methylation ( < .0001). Multivariate regression analysis showed that both poor metabolizers and rs34394661 AA ( = .009) genotype were associated with higher odds for HTPR in the overall samples. In contrast, cg06300880 methylation ( = .002) caused lower odds for HTPR in patients with non-ST elevation myocardial infarction-ACS.
CONCLUSION
cg06300880 and CpG-single-nucleotide polymorphism rs34394661 could be independent predictors of HTPR with clopidogrel therapy.
背景
氯吡格雷和阿司匹林双重抗血小板治疗是接受经皮冠状动脉介入治疗患者的主要治疗方法。然而，氯吡格雷反应的个体差异显著，治疗期高血小板反应性（HTPR）会增加经皮冠状动脉介入治疗后血栓事件的风险。
目的
我们研究了DNA甲基化中可能影响氯吡格雷反应的新的可及因素。
方法
采用甲基化850K芯片检测DNA甲基化水平。在330例急性冠状动脉综合征（ACS）患者中，给予氯吡格雷300mg负荷剂量或至少5天每日75mg维持剂量后，测定血小板反应指数（PRI）。
结果
总体而言，32个发现样本显示出氯吡格雷反应极端：16例为HTPR（PRI>75%），16例为非HTPR（PRI<26%）。总体而言，两组之间观察到61个差异甲基化位点（DML）。大多数位于基因组的开放海域和基因间区域。在验证阶段，HTPR显示cg06300880甲基化水平较低。rs34394661 AA基因型携带者，即cg06300880位点的CpG单核苷酸多态性，显示HTPR的几率增加（ACS患者的总体比值比=7.31，95%CI：1.69-31.59，P=.008；非ST段抬高型心肌梗死-ACS：比值比=12.69，95%CI：1.68-96.08，P=.01），且cg06300880甲基化降低（P<.0001）。多变量回归分析显示，在总体样本中，慢代谢者和rs34394661 AA（P=.009）基因型均与HTPR的较高几率相关。相比之下，cg06300880甲基化（P=.002）导致非ST段抬高型心肌梗死-ACS患者HTPR的几率较低。
结论
cg06300880和CpG单核苷酸多态性rs34394661可能是氯吡格雷治疗中HTPR的独立预测因子。
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