Causal associations between neuroinflammation-related genes and intracerebral hemorrhage: an integrated study of Mendelian Randomization and gene functional analysis

Intracerebral hemorrhage (ICH) is a life-threatening stroke subtype where neuroinflammation plays a crucial role. However, the genetic basis for neuroinflammation in ICH remains unclear.

This study used Mendelian Randomization (MR) to investigate the causal impact of neuroinflammation-related genes on ICH risk. A two-sample MR analysis was conducted using genetic variants from large-scale genome-wide association studies (GWAS). The primary analytical methods included the inverse variance weighted (IVW) approach, supplemented by MR-Egger regression and the weighted median method. Protein-protein interaction (PPI) network analysis, Gene Ontology (GO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were employed to explore the biological mechanisms underlying these associations.

Elevated expression of the CHUK gene was significantly associated with increased ICH risk (OR = 1.17, 95% CI 1.02-1.35, p = 0.0245 in the Ebi-ICH dataset; OR = 1.25, 95% CI 1.03-1.52, p = 0.0252 in the Finn-ICH dataset). Similarly, the CTLA4 gene showed a strong association with ICH (OR = 1.29, 95% CI 1.10-1.52, p < 0.01 in the Ebi-ICH dataset; OR = 1.23, 95% CI 1.02-1.47, p = 0.0264 in the Finn-ICH dataset). These results suggest that these genes contribute to ICH through mechanisms involving the NF-κB signaling pathway and immune regulation.

The findings reveal a significant genetic influence of CHUK and CTLA4 on ICH risk, provide potential targets for future therapeutic interventions, which could lead to the development of more effective treatment strategies for ICH.