A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke
A predictive clinical-genetic model of tissue plasminogen activator response in acute ischemic stroke
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DOI：
10.1002/ana.23664
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发表时间：
2012-11-01
影响因子：
11.2
通讯作者：
Montaner, Joan
中科院分区：
文献类型：
--
作者：
del Rio-Espinola, Alberto;Fernandez-Cadenas, Israel;Montaner, Joan
目的：缺血性脑卒中急性期对组织型纤溶酶原激活剂（t-PA）治疗的反应存在广泛的个体差异。我们的目的是找到与t-PA后出血性转化（HT）和死亡率相关的遗传变异。然后我们建立了一个预测t-PA反应的临床遗传学模型。方法：我们的前瞻性研究使用SNPlex对3个患者队列中97个候选基因的140个单核苷酸多态性（SNP）进行基因分型。队列包括1，172例接受t-PA治疗的患者;通过系统性脑计算机断层扫描评估，其中20.9%发生HT，10.6%死亡。通过逻辑回归（LR）生成预测模型。功能研究包括真实的时间定量聚合酶链反应、浊度测定法和α 2-巨球蛋白（A2 M）的蛋白质印迹法以及凝血因子XII（FXII）的活化部分凝血活酶时间测量。结果如下：复制分析显示，A2 M的rs669（Val 1000 Ile）与HT相关，F12的rs 1801020（-4C>T）与院内死亡相关。rs669 SNP耐受HT的Bonferroni校正（p <3.57 E-4）。基于LR的评分预测HT发生率（p = 9.13E-15）和住院死亡率（p = 8.7E-9），并在独立队列中得到验证。Val 1000 Ile改变了基线和t-PA输注后的A2 M血清水平，但不影响mRNA表达或蛋白质结构; -4C>T在t-PA治疗前后均影响FXII活性。解释：两种功能多态性与t-PA安全性一致相关。我们验证的LR评分预测t-PA在西班牙人群中的安全性。神经网络2012;72：716729
Objective: Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinicalgenetic model for predicting t-PA response. Methods: Our prospective study used SNPlex to genotype 140 single nucleotide polymorphisms (SNPs) from 97 candidate genes in 3 patient cohorts. The cohorts included 1,172 patients who were treated with t-PA; 20.9% of them developed HT as evaluated by systematic brain computed tomography scan, and 10.6% died. A predictive model was generated by logistic regression (LR). Functional studies included real time quantitative polymerase chain reaction, nephelometry, and Western blot for alpha-2-macroglobulin (A2M) and activated partial thromboplastin time measurement for coagulation factor XII (FXII). Results: Replication analysis revealed that the SNP rs669 (Val1000Ile) in A2M was associated with HT, and rs1801020 (-4C>T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p < 3.57E-4). LR-based scores predicted HT occurrence (p = 9.13E-15) and in-hospital mortality (p = 8.7E-9) and were validated in an independent cohort. Val1000Ile modified A2M serum levels at baseline and after t-PA infusion, but not mRNA expression or protein structure; -4C>T affected FXII activity both prior to and after t-PA treatment. Interpretation: Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population. ANN NEUROL 2012;72:716729