Genetically prioritized plasma proteins in intracerebral hemorrhage identified by Mendelian randomization with functional evidence of neuronal vulnerability

Am J Transl Res. 2026 Apr 25;18(4):3640-3653. doi: 10.62347/TBCS8286. eCollection 2026.

ABSTRACT

OBJECTIVES: Our study aims to assess the causal association between plasma proteins, immune cell phenotypes and intracerebral hemorrhage (ICH) and explore their downstream biological correlation.

METHODS: We adopted the two-sample Mendelian randomization (MR) approach. The analysis evaluated the effects of more than 4,000 plasma proteins and 731 immune cell phenotypes on the risk of ICH. Bidirectional MR, mediation effect and sensitivity analysis confirm the causal relationship. We transfect SH-SY5Y neuroblastoma cells and overexpress AHSP or ITGB5 to observe possible function effects.

RESULTS: MR analysis linked 299 plasma proteins with ICH (P < 0.05), of which 60 proteins showed strong statistical support (P < 0.01) and there was no reverse causality. Eighteen types of immune cells also affect ICH risk. Mediation analysis identified 6 causal axes to link specific proteins (IGF1R, NT5E/CD73, ITGB5, CUZD1, and AHSP) with ICH, in which different B cell and T cell subgroups play a key intermediary role. Overexpression of AHSP or ITGB5 inhibits the proliferation and migration of SH-SY5Y cells while promoting their apoptosis.

CONCLUSIONS: We combined genetics and laboratory data to find that several plasma proteins affect ICH risk. The immune pathway seems to link these proteins with ICH. Although we acknowledge the limitations of MR analysis and in vitro experimental frameworks, the apoptosis promoting effects of AHSP and ITGB5 provide preliminary functional evidence of their role in neuronal damage. Targeting these pathways may provide new strategies for intervention in ICH.

PMID:42170445 | PMC:PMC13186738 | DOI:10.62347/TBCS8286