Faculty of Medicine, Institute of Human Genetics, University of Belgrade, Belgrade, Serbia.
Neurology Clinic, Clinical Center of Serbia, Belgrade, Serbia.
Pharmacotherapy. 2021 Jul;41(7):562-571. doi: 10.1002/phar.2532. Epub 2021 May 27.
Levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) influence recombinant tissue plasminogen activator (rtPA) therapy response in patients with acute ischemic stroke (AIS). Serum levels of MMPs and TIMPs along with the expression of genes coding these proteins are related to the recovery and appearance of adverse effects (AE) after AIS. Consequently, it is important to explore whether polymorphisms in regulatory sequences of MMPs and TIMPs are associated with rtPA response in AIS patients.
To determine whether selected polymorphic variants within MMP-2, MMP-9, and TIMP-2 genes may influence rtPA therapy response with regard to outcomes in patients with AIS and the occurrence of AE.
Our study included 166 patients suffering AIS, treated with rtPA. Patients' recovery was estimated using the Modified Rankin Scale (mRS) 3 months after the AIS occurred. Favorable outcome was defined with scores 0-1 and poor outcome with scores 2-6. Genotyping was performed using real-time PCR (rs243866, rs243865, rs243864, rs2277698, and rs8179090) and PCR-RFLP (rs2285053, rs3918242) methods. Additionally, rtPA AE were followed during the hospitalization.
There was no significant association between genotypes and alleles of selected polymorphisms and rtPA therapy response measured through the decrease of the mRS score in patients with AIS. Intracranial hemorrhage, as well as parenchymal hematoma type 2, was significantly more frequent in patients with TT genotype of the MMP-9-1562C/T polymorphism (p = 0.047, p = 0.011, respectively). Patients with intracranial hemorrhages after rtPA were significantly more likely to have the TT genotype of TIMP-2-303C/T polymorphism and the TT genotype of MMP-9-1562C/T polymorphism (p < 0.001).
TT genotype of the MMP-9-1562C/T polymorphism may be a risk factor for rtPA-induced hemorrhagic complications after AIS.
基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs）的水平影响急性缺血性脑卒中（AIS）患者重组组织型纤溶酶原激活剂（rtPA）治疗的反应。MMPs 和 TIMPs 的血清水平以及编码这些蛋白的基因的表达与 AIS 后恢复和不良事件（AE）的出现有关。因此，探索 MMPs 和 TIMPs 的调节序列中的多态性是否与 AIS 患者的 rtPA 反应相关非常重要。
确定 MMP-2、MMP-9 和 TIMP-2 基因中选定的多态性变体是否可能影响 AIS 患者 rtPA 治疗的反应，以及与 AE 的发生有关。
我们的研究纳入了 166 名患有 AIS 并接受 rtPA 治疗的患者。患者的恢复情况使用改良 Rankin 量表（mRS）在 AIS 发生后 3 个月进行评估。良好的结局定义为评分 0-1，不良结局定义为评分 2-6。使用实时 PCR（rs243866、rs243865、rs243864、rs2277698 和 rs8179090）和 PCR-RFLP（rs2285053、rs3918242）方法进行基因分型。此外，在住院期间还观察了 rtPA 的 AE。
在 AIS 患者中，通过 mRS 评分下降来衡量的 rtPA 治疗反应与选定多态性的基因型和等位基因之间没有显著关联。与 MMP-9-1562C/T 多态性的 CC 基因型相比，MMP-9-1562C/T 多态性的 TT 基因型患者颅内出血和 2 型脑实质血肿的发生率明显更高（p=0.047，p=0.011）。rtPA 后发生颅内出血的患者更有可能具有 TIMP-2-303C/T 多态性的 TT 基因型和 MMP-9-1562C/T 多态性的 TT 基因型（p<0.001）。
MMP-9-1562C/T 多态性的 TT 基因型可能是 AIS 后 rtPA 诱导的出血性并发症的危险因素。
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