Integrating Proteomics and Mendelian Randomization to Evaluate HGF as a Potential Mediator of Stroke Risk Factors.

Purpose

Stroke prediction remains suboptimal. We aimed to identify plasma proteins associated with stroke risk and evaluate their potential as clinical biomarkers and causal mediators. EXPERIMENTAL

Design

We used a multitiered proteomic approach in the UK Biobank (UKB). In a matched nested case-control study (672 cases, 2,688 controls), 2,920 proteins were analyzed. Findings were internally validated in the UKB-PPP cohort and cross-validated using genetic instruments from seven large-scale protein GWAS meta-analyses. Mendelian randomization (MR) and mediation analyses were employed to assess causality.

Results

We identified 122 proteins significantly associated with stroke risk. A 122-protein panel improved the C-index from 0.610 to 0.693. MR analysis provided genetic evidence supporting an association between higher genetically predicted Hepatocyte Growth Factor (HGF) levels and stroke risk (OR 1.18, 95% CI 1.09-1.28). Mediation analysis indicated that HGF mediated 39.15% of the effect of weight and 37.28% of waist circumference on stroke risk.

Conclusions

AND CLINICAL RELEVANCE Our findings support HGF as a potential mediator linking metabolic risk factors to stroke. The identified protein panel offers a robust tool for stroke risk stratification and highlights HGF as a biologically plausible candidate for therapeutic intervention.