Neurovascular Research Laboratory and Neurovascular Unit, Departments of Neurology and Medicine Departments, Autonomous University of Barcelona, Passeig Vall d'Hebron 119-129, Barcelona, Spain.
Ann Neurol. 2012 Nov;72(5):716-29. doi: 10.1002/ana.23664.
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 clinical-genetic model for predicting t-PA response.
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).
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.
Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population.
在缺血性脑卒中急性期，组织型纤溶酶原激活剂（t-PA）的治疗存在广泛的个体间差异。我们旨在寻找与 t-PA 治疗后出血性转化（HT）和死亡率相关的遗传变异。然后，我们生成了一个用于预测 t-PA 反应的临床遗传模型。
我们的前瞻性研究使用 SNPlex 对来自 97 个候选基因的 140 个单核苷酸多态性（SNP）进行基因分型，在 3 个患者队列中进行。这些队列包括 1172 例接受 t-PA 治疗的患者；其中 20.9%的患者经系统脑计算机断层扫描评估发生 HT，10.6%的患者死亡。通过逻辑回归（LR）生成预测模型。功能研究包括实时定量聚合酶链反应、散射比浊法和 Western blot 用于α-2-巨球蛋白（A2M），以及用于凝血因子 XII（FXII）的活化部分凝血活酶时间测量。
复制分析表明，A2M 中的 SNP rs669（Val1000Ile）与 HT 相关，F12 中的 rs1801020（-4C>T）与住院期间死亡相关。rs669 SNP 经 Bonferroni 校正后仍与 HT 相关（p < 3.57E-4）。基于 LR 的评分预测 HT 发生（p = 9.13E-15）和住院期间死亡率（p = 8.7E-9），并在独立队列中得到验证。Val1000Ile 修饰了基线和 t-PA 输注后的 A2M 血清水平，但不影响 mRNA 表达或蛋白质结构；-4C>T 影响 t-PA 治疗前后的 FXII 活性。
两个功能多态性与 t-PA 的安全性一致。我们验证的基于 LR 的评分可预测西班牙人群中 t-PA 的安全性。
