An integrative genomic framework to identify remote ischemic preconditioning-responsive genes associated with stroke...

Area of Science:

• Genomics and Molecular Biology
• Translational Medicine
• Neuroscience

Background:

• Remote ischemic preconditioning (RIPC) shows potential for reducing stroke injury but lacks defined molecular mechanisms and human translatability.
• The causal role of RIPC-induced gene programs in human stroke risk reduction is unclear.
• Establishing a translational framework is crucial for linking animal model findings to human stroke genetics.

Purpose of the Study:

• To establish a translational framework linking RIPC-induced gene regulation in mice to causal genetic and epigenetic determinants of stroke risk in humans.
• To identify RIPC-regulated beneficial genes (RBGs) with potential roles in stroke risk reduction.
• To evaluate the predictive potential of RBG signatures for stroke risk.

Main Methods:

• Multi-tissue transcriptomic profiling in a mouse transient middle cerebral artery occlusion (tMCAO) model.
• Integration of mouse differentially expressed genes with human orthologs, expression quantitative trait loci (eQTL) data, and stroke genome-wide association studies (GWAS).
• Mendelian randomization (MR) analysis to identify RBGs and evaluate DNA methylation effects; machine learning for predictive modeling.

Main Results:

• Identified 23 core RBGs causally associated with reduced stroke risk, linked to neuroprotection, immune modulation, and tissue repair pathways.
• MR supported causal effects of RBG-associated DNA methylation sites on stroke risk.
• Predictive modeling achieved high translational performance (AUC=0.97); experimental validation confirmed RIPC upregulated key RBGs, reduced infarct volume, and improved neurological outcomes.

Conclusions:

• Presents an integrative framework linking RIPC transcriptomic responses to human genetic associations via RBGs.
• Identifies candidate pathways for ischemic injury modulation.
• Provides a basis for future translational studies on RIPC and stroke risk reduction.