ABCC2 as a drug target for post-stroke recovery: Evidence from Mendelian randomization and colocalization analyses

Ischemic stroke imposes a substantial burden due to long-term neurological disability and high mortality. Despite advancements in acute treatment, therapeutic strategies for post-stroke recovery remain limited.

We conducted a two-sample Mendelian randomization (MR) using summary statistics of post-stroke functional outcome from the Genetics of Ischemic Stroke Functional Outcome (GISCOME) network and cis-expression quantitative trait loci (cis-eQTLs) of druggable genes from the eQTLGen Consortium. Bayesian colocalization analysis was performed to assess the shared genetic architecture between gene expression and post-stroke functional outcome. Follow-up analyses included phenome-wide association analysis, collider bias evaluation, protein-protein interaction (PPI) network construction, functional enrichment analysis, and drug candidate prediction via Connectivity Map (CMap) analysis.

Two-sample MR identified 15 genes associated with post-stroke functional outcome, of which five were validated in unadjusted models. Summary-data-based MR (SMR) analysis further confirmed three genes, with ABCC2 demonstrating strong colocalization evidence (PPH4 = 0.843) with post-stroke functional outcome. Results of phenome-wide association analysis showed that ABCC2 was associated with direct bilirubin. Functional analyses showed that ABCC2 expression signatures were enriched in coagulation regulation and lipid efflux pathways. CMap analysis predicted candidate drugs that modulate ABCC2-related gene expression signatures.

This study provides genetic evidence supporting ABCC2 as a druggable target for post-stroke recovery. Our findings offer insights into the underlying mechanisms and highlight the potential for drug repurposing, providing a scientific basis for future therapeutic development in ischemic stroke rehabilitation.