氯吡格雷相关基因变异与缺血性脑卒中患者氯吡格雷治疗后早期神经功能恶化
Variants in clopidogrel-relevant genes and early neurological deterioration in ischemic stroke patients receiving clopidogrel.
机构信息
Department of Neurology, the People's Hospital of Deyang City, Deyang, 618000, Sichuan, China.
Department of Neurology, the Third Affiliated Hospital of Wenzhou Medical University, 108 Wanson Road, Ruian City, Wenzhou, 325200, Zhejiang, China.
出版信息
BMC Neurol. 2020 Apr 28;20(1):159. doi: 10.1186/s12883-020-01703-6.
BACKGROUND
Early neurological deterioration (END) is common in acute ischemic stroke (IS). However, the underlying mechanisms for END are unclear. The aim of this study was to evaluate the associations of 16 variants in clopidogrel-relevant genes and interactions among these variants with END in acute IS patients receiving clopidogrel treatment.
METHODS
We consecutively enrolled 375 acute IS patients between June 2014 and January 2015. Platelet aggregation was measured on admission and after the 7-10 days of clopidogrel treatment. The 16 variants in clopidogrel-relevant genes were examined using mass spectrometry. The primary outcome was END within the 10 days of admission. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR) methods.
RESULTS
Among the 375 patients, 95 (25.3%) patients developed END within the first 10 days of admission. Among the 16 variants, only CYP2C192 (rs4244285) AA/AG was associated with END using single-locus analytical approach. GMDR analysis revealed that there was a synergistic effect of gene-gene interactions among CYP2C192 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 on the risk for END. The high-risk interactions among the three variants were associated with the higher platelet aggregation and independent predictor for END after adjusting for the covariates (hazard ratio: 2.82; 95% confidence interval: 1.36-7.76; P = 0.003).
CONCLUSIONS
END is very common in patients with acute IS. The mechanisms leading to END are most likely multifactorial. Interactions among CYP2C19*2 rs4244285, P2Y12 rs16863323, and GPIIIa rs2317676 may confer a higher risk for END. It was very important to modify clopidogrel therapy for the patients carrying the high-risk interactive genotypes.
CLINICAL TRIAL REGISTRATION INFORMATION
The study described here is registered at http://www.chictr.org/ (unique Identifier: ChiCTR-OCH-14004724). The date of trial registration was May 30, 2014.
背景
急性缺血性脑卒中（IS）患者常出现早期神经功能恶化（END）。然而，END 的潜在机制尚不清楚。本研究旨在评估氯吡格雷相关基因中的 16 个变异体以及这些变异体之间的相互作用与接受氯吡格雷治疗的急性 IS 患者 END 的相关性。
方法
我们连续纳入了 2014 年 6 月至 2015 年 1 月期间的 375 例急性 IS 患者。入院时及氯吡格雷治疗 7-10 天后测量血小板聚集率。采用质谱法检测氯吡格雷相关基因中的 16 个变异体。主要结局为入院后 10 天内发生 END。采用广义多因素降维（GMDR）方法分析基因-基因相互作用。
结果
在 375 例患者中，95 例（25.3%）患者在入院后 10 天内发生 END。单因素分析显示，CYP2C192(rs4244285)AA/AG 与 END 相关。GMDR 分析显示，CYP2C192(rs4244285)、P2Y12(rs16863323)和 GPIIIa(rs2317676)之间的基因-基因相互作用存在协同效应，与 END 的风险相关。在调整了协变量后，三个变异体的高风险相互作用与较高的血小板聚集率相关，是 END 的独立预测因子（风险比：2.82；95%置信区间：1.36-7.76；P=0.003）。
结论
急性 IS 患者 END 非常常见。导致 END 的机制很可能是多因素的。CYP2C19*2(rs4244285)、P2Y12(rs16863323)和 GPIIIa(rs2317676)之间的相互作用可能使 END 的风险增加。对于携带高危相互作用基因型的患者，调整氯吡格雷治疗非常重要。
临床试验注册信息
本研究描述的内容在中国临床试验注册中心（http://www.chictr.org/）注册（注册号：ChiCTR-OCH-14004724）。试验注册日期为 2014 年 5 月 30 日。
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