Department of Neurology, Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China.
Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology Wuhan China.
J Am Heart Assoc. 2024 Aug 20;13(16):e034749. doi: 10.1161/JAHA.124.034749. Epub 2024 Aug 9.
Stroke is a leading cause of death worldwide, with a lack of effective treatments for improving the prognosis. The aim of the present study was to identify novel therapeutic targets for functional outcome after ischemic stroke .
Cis-expression quantitative trait loci data for druggable genes were used as instrumental variables. The primary outcome was the modified Rankin Scale score at 3 months after ischemic stroke, evaluated as a dichotomous variable (3-6 versus 0-2) and also as an ordinal variable. Drug target Mendelian randomization, Steiger filtering analysis, and colocalization analysis were performed. Additionally, phenome-wide Mendelian randomization analysis was performed to identify the safety of the drug target genes at the genetic level. Among >2600 druggable genes, genetically predicted expression of 16 genes (, , , , , , , , , , , , , , , and ) demonstrated the causal associations with ordinal modified Rankin Scale (<1.892×10) or poor functional outcome (modified Rankin Scale 3-6 versus 0-2, <1.893×10). Steiger filtering analysis suggested potential directional stability (<0.05). Colocalization analysis provided further support for the associations between genetically predicted expression of , , , and with functional outcome after ischemic stroke. Furthermore, phenome-wide Mendelian randomization revealed additional beneficial indications and few potential safety concerns of therapeutics targeting , , , and , but the robustness of these results was limited by low power.
The present study revealed 4 candidate therapeutic targets for improving functional outcome after ischemic stroke, while the underlying mechanisms need further investigation.
脑卒中是全球范围内主要的致死病因之一，目前缺乏改善预后的有效治疗方法。本研究旨在寻找改善缺血性脑卒中后功能结局的新治疗靶点。
使用药物靶点顺式表达数量性状基因座数据作为工具变量。主要结局为缺血性脑卒中后 3 个月时改良 Rankin 量表评分，评估为二分类变量（3-6 与 0-2）和有序变量。进行药物靶点孟德尔随机化、Steiger 过滤分析和共定位分析。此外，还进行了表型全基因组孟德尔随机化分析，以在遗传水平上评估药物靶点基因的安全性。在 >2600 个可药物治疗的基因中，16 个基因（,,,,,,,,,,,,,, 和 ）的遗传预测表达与有序改良 Rankin 量表（<1.892×10）或不良功能结局（改良 Rankin 量表 3-6 与 0-2，<1.893×10）存在因果关联。Steiger 过滤分析提示潜在的方向性稳定性（<0.05）。共定位分析为缺血性脑卒中后基因预测表达与功能结局之间的关联提供了进一步支持。此外，表型全基因组孟德尔随机化显示针对 、 、 、和 的治疗具有额外的有益指征和少数潜在的安全问题，但这些结果的稳健性受到效力低的限制。
本研究揭示了 4 个候选治疗靶点，可改善缺血性脑卒中后的功能结局，但其潜在机制仍需进一步研究。
