背景:缺血性卒中(IS)每年都更常见,情况很严重,预后不良.新,高效,由于早期治疗尤其是预防和再灌注是降低不良预后发生的关键,因此迫切需要安全的治疗目标。一般来说,循环蛋白是有吸引力的治疗靶点,本研究旨在使用多中心孟德尔随机化(MR)方法,在血浆和脑脊液(CSF)蛋白中确定预防和治疗IS的潜在药理学靶点.
方法:首先,通过MR评估了734种血浆和151种CSF蛋白的遗传工具与MEGASTROKE联盟的IS之间的因果关系,以确定前瞻性治疗靶点.然后,对于额外的验证,来自deCODE财团和Fenland财团的血浆蛋白,以及来自FinnGen队列的ISGWAS数据,ISGC财团和英国生物银行,被雇用。使用荟萃分析对上述可能的药理学靶标进行了全面评估。然后通过使用几种技术的灵敏度分析证实了MR结果的鲁棒性,例如双向MR分析,Steiger滤波,和贝叶斯共同本地化。最后,使用蛋白质-蛋白质相互作用(PPI)网络等方法来研究推定的药物靶标与治疗剂之间的关系。
结果:我们发现了3种蛋白质,这些蛋白质可能是IS的有希望的治疗靶标,并且符合Bonferroni校正(P<0.05/885=5.65×10-5)。激肽释放酶(OR=0.41,95CI:0.27-0.63,P=3.61×10-5),一种在脑脊液中发现的蛋白质,对IS有10倍的保护作用,而每个SD的血浆蛋白SWAP70(OR=0.85,95CI:0.80-0.91,P=1.64×10-6)和MMP-12(OR=0.92,95CI:0.89-0.95,P=4.49×10-6)在IS中起保护作用。Prekallikrein,MMP-12,SWAP70在FinnGen队列和ISGC数据库中复制。MMP-12(OR=0.93,95CI:0.91-0.94,P<0.001),SWAP70(OR=0.92,95CI:0.90-0.94,P<0.001),和前激肽释放酶(OR=0.53,95CI:0.33-0.72,P<0.001)可能都是IS的可行靶标,根据合并的荟萃分析结果。此外,没有发现反向因果关系的证据,和贝叶斯共定位显示MMP-12(PPH4=0.995),SWAP70(PPH4=0.987)和前激肽释放酶(PPH4=0.894)与IS共享相同的变体,支持上述因果关系的稳健性。前激肽释放酶和MMP-12与目前治疗IS的靶蛋白相关。其中,Lanadelumab,一种新的药物,其靶蛋白是激肽释放酶,可能是一种有希望的治疗IS的新药。
结论:前激肽释放酶,MMP-12和SWAP70与IS的风险有因果关系。此外,MMP-12和前激肽释放酶可能被视为有希望的IS医学干预治疗靶标。
BACKGROUND: Ischemic stroke (IS) is more common every year, the condition is serious, and have a poor prognosis. New, efficient, and safe therapeutic targets are desperately needed as early treatment especially prevention and reperfusion is the key to lowering the occurrence of poorer prognosis. Generally circulating proteins are attractive therapeutic targets, this study aims to identify potential pharmacological targets among plasma and cerebrospinal fluid (CSF) proteins for the prevention and treatment of IS using a multicenter Mendelian randomization (MR) approach.
METHODS: First, the genetic instruments of 734 plasma and 151 CSF proteins were assessed for causative connections with IS from MEGASTROKE consortium by MR to identify prospective therapeutic targets. Then, for additional validation, plasma proteins from the deCODE consortium and the Fenland consortium, as well as IS GWAS data from the FinnGen cohort, the ISGC consortium and UK biobank, were employed. A thorough evaluation of the aforementioned possible pharmacological targets was carried out using meta-analysis. The robustness of MR results was then confirmed through sensitivity analysis using several techniques, such as bidirectional MR analysis, Steiger filtering, and Bayesian colocalization. Finally, methods like Protein-Protein Interaction (PPI) Networking were utilized to investigate the relationship between putative drug targets and therapeutic agents.
RESULTS: The authors discovered three proteins that may function as promising therapeutic targets for IS and meet the Bonferroni correction ( P <0.05/885=5.65×10 -5 ).
Prekallikrein (OR=0.41, 95% CI: 0.27-0.63, P =3.61×10 -5 ), a protein found in CSF, has a 10-fold protective impact in IS, while the plasma proteins SWAP70 (OR=0.85, 95% CI: 0.80-0.91, P =1.64×10 -6 ) and MMP-12 (OR=0.92, 95% CI: 0.89-0.95, P =4.49×10 -6 ) of each SD play a protective role in IS.
Prekallikrein, MMP-12, SWAP70 was replicated in the FinnGen cohort and ISGC database. MMP-12 (OR=0.93, 95% CI: 0.91-0.94, P <0.001), SWAP70 (OR=0.92, 95% CI: 0.90-0.94, P <0.001), and prekallikrein (OR=0.53, 95% CI: 0.33-0.72, P <0.001) may all be viable targets for IS, according to the combined meta-analysis results. Additionally, no evidence of reverse causality was identified, and Bayesian colocalization revealed MMP-12 (PPH 4 =0.995), SWAP70 (PPH 4 =0.987), and prekallikrein (PPH 4 =0.894) shared the same variant with IS, supporting the robustness of the aforementioned causation.
Prekallikrein and MMP-12 were associated with the target protein of the current treatment of IS. Among them, Lanadelumab, a new drug whose target protein is a
prekallikrein, may be a promising new drug for the treatment of IS.
CONCLUSIONS: The
prekallikrein, MMP-12, and SWAP70 are causally associated with the risk of IS. Moreover, MMP-12 and prekallikrein may be treated as promising therapeutic targets for medical intervention of IS.