Identification of Six Potential Therapeutic Targets Common to Ischemic Stroke and Vascular Dementia: Genetic Insights From an Integrated Bioinformatics Analysis

TL;DR

This study identifies six plasma proteins that are linked to both ischemic stroke and vascular dementia, offering new therapeutic targets based on genetic and experimental evidence.

Contribution

The study integrates genetic and experimental approaches to identify six plasma proteins with causal roles in both ischemic stroke and vascular dementia.

Findings

Six plasma proteins (CD40, Furin, CD300LF, F11, F2, and ITGAV) show causal relationships with both ischemic stroke and vascular dementia.

CD40 and Furin associations are mediated through atrial fibrillation or diastolic blood pressure.

In vivo experiments confirm CD40, Furin, F11, and ITGAV as causal factors in ischemic stroke and vascular dementia.

Abstract

The aim was to investigate the potential therapeutic targets for ischemic stroke (IS) and vascular dementia (VD).

We assessed the causal effects of 2943 plasma proteins on IS and VD using a two‐sample Mendelian randomization (MR) framework. Results were validated via summary data‐based MR (SMR) analysis. A two‐step mediation MR analysis was conducted to elucidate potential causal mechanisms by which plasma proteins influence IS and VD through risk factors. We performed a phenome‐wide association study (PheWAS) MR analysis to explore side effects and additional indications for IS and VD‐associated plasma proteins. We established middle cerebral artery occlusion and reperfusion (MCAO/R) and VD rat models to verify potential therapeutic targets for IS and VD.

Genetically predicted plasma levels of six proteins demonstrated causal relationships with both IS and VD. SMR analysis validated four of these proteins (CD40, F11, F2, and Furin). Atrial fibrillation (AF), type 2 diabetes (T2D), low‐density lipoprotein (LDL), and diastolic blood pressure (DBP) were causally associated with the risk of IS and VD, indicating common risk factors. CD40 and Furin associations with IS and VD appeared to be mediated by AF or DBP. The mechanisms of action of IS‐ and VD‐related proteins primarily involve the complement and coagulation cascade. In vivo experiments confirmed that CD40, Furin, F11, and integrin alpha‐V (ITGAV) were causally associated with IS and VD.

Our findings illuminate causal pathways and potential therapeutic targets for IS and VD. We identified six plasma proteins with causal relationships to IS, VD, and their risk factors, providing insights into using these proteins as therapeutic targets for IS and VD.

This graphical abstract summarizes a multi‐layered analytical framework integrating cis‐eQTLs, UKB‐PPP proteomics, and multivariable Mendelian randomization to dissect the causal links between circulating proteins, vascular risk factors, ischemic stroke (IS), and vascular dementia (VD). After applying stringent selection criteria for instrumental variables, primary MR analyses identified six genetically predicted plasma proteins (CD40, Furin, CD300LF, F11, F2, and ITGAV) with significant causal effects on both IS and VD. Follow‐up PheWAS and transcriptomic analyses further validated protein‐specific phenotypic associations and molecular pathways. Finally, in vivo experiments confirmed the causal influence of CD40, Furin, F11, and ITGAV on IS and VD, supporting these proteins as potential therapeutic targets for preventing brainvascular multimorbidity.

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