Associations Between Stroke and Vascular Dementia Combing Mendelian Randomization with Network Pharmacology

Background: Stroke and vascular dementia (VaD) are major causes of death and disability worldwide, and there is a complex interplay between them. In this study, we applied the method of Mendelian randomization (MR) and network pharmacology to uncover and elucidate these mechanisms.

Methods: We employed single nucleotide polymorphisms that exhibit strong associations with stroke and VaD as instrumental variables for MR analysis. Our bidirectional MR analyses were conducted using 3 robust methods: inverse variance weighting, weighted median, Weighted mode and MR-Egger regression. Additionally, we performed sensitivity analyses to assess heterogeneity, sensitivity, and stability levels. Furthermore, we curated and screened targets relevant to stroke and VaD and subsequently carried out gene ontology and KEGG pathway enrichment analyses. Finally, network pharmacology approaches were utilized to explore potential mechanisms underlying stroke and VaD.

Results: The results of the inverse variance weighted analysis demonstrate a significant positive causal relationship between stroke and VaD (OR = 2.06, 95% confidence interval [CI] = 1.17-3.61, P = .01). Conversely, no evidence suggests that VaD increases the risk of stroke. Network pharmacology analysis reveals a total of 222 common targets shared by both conditions, with particular emphasis on peptide tyrosine phosphorylation pathways, including those associated with resistance to EGFR tyrosine kinase inhibitors and the AGE-RAGE signaling pathway.

Conclusions: Our MR analysis is based on available summary statistics from genome-wide association studies to support a causal relationship between stroke and VaD. Stroke may contribute to VaD through peptide tyrosine phosphorylation-related biological processes.