Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain. Electronic address: https://twitter.com/FabregaGallego.
Genomics of Complex Disease Group, Institut de Recerca Sant Pau (IR SANT PAU), Barcelona, Spain.
J Thromb Haemost. 2024 Apr;22(4):936-950. doi: 10.1016/j.jtha.2023.11.027. Epub 2023 Dec 15.
Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient's prognosis.
To investigate the association between genetically determined natural hemostatic factors' levels and increased risk of HT after r-tPA treatment.
Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT.
Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10; rs1421067 (CHD9), P = 1.81 × 10; and rs34780449, near ROBO1 gene, P = 1.64 × 10. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [-0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05).
We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.
溶栓重组组织纤溶酶原激活物（r-tPA）治疗是缺血性脑卒中急性期唯一可用的药物干预手段。这种治疗方法与颅内出血的风险增加有关，称为出血性转化（HTs），这会使患者的预后恶化。
研究遗传决定的天然止血因子水平与 r-tPA 治疗后 HT 风险增加之间的关系。
利用 r-tPA 治疗后 HT 风险的全基因组关联研究数据和 7 种止血因子（因子[F]VII、VIII、血管性血友病因子[VWF]、FXI、纤维蛋白原、纤溶酶原激活物抑制剂-1 和组织型纤溶酶原激活物）的数据，我们进行了局部和全局遗传相关性估计多性状分析以及止血因子与 HT 之间的 colocalization 和 2 样本 Mendelian 随机化分析。
局部相关性确定了染色体 16 上具有共同协方差的基因组区域：纤维蛋白原-HT，P=2.45×10。纤维蛋白原-HT 之间的多性状分析揭示了 3 个同时调节循环纤维蛋白原水平和 HT 风险的位点：rs56026866（PLXND1），P=8.80×10；rs1421067（CHD9），P=1.81×10；rs34780449，位于 ROBO1 基因附近，P=1.64×10。VWF-HT 之间的多性状分析显示，rs10942300（ZNF366）在 r-tPA 后调节 VWF 和 HT 方面存在新的共同关联，P=1.81×10。Mendelian 随机化分析未发现显著的因果关联，尽管 FXI-HT 存在名义关联（逆方差加权估计[SE]，0.07[-0.29 至 0.00]；比值比，0.87；95%CI，0.75-1.00；原始 P=0.05）。
我们在 r-tPA 治疗后止血因子和 HT 之间发现了 4 个共同的位点，这表明纤维蛋白原和 VWF 水平与 HT 之间存在共同的调节机制。需要进一步的研究来确定纤维蛋白原对 HT 风险的可能中介作用。
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