Mendelian randomization analyses explore the relationship between cathepsins and stroke

Abstract

Abstract Background：Our current understanding of cathepsins' role in stroke is limited. To delve deeper, we're using R software for bidirectional and multivariate Mendelian Randomization (MR) studies. Method：We used public Genome-Wide Association Studies (GWAS). Data on cathepsins (n=3,301) came from the INTERVAL study; stroke data (n=446,696) from the MEGASTROKE consortium, including ischemic stroke (IS) (n=440,328) and its subtypes, and intracerebral hemorrhage (ICH) (n=3,026). Our main analytical method was Inverse Variance Weighting (IVW). Supplementary methods included Weighted Median, MR-Egger, Simple Mode, and Weighted Mode. Heterogeneity was assessed via Cochran Q test, and pleiotropy through MR-Egger intercept and MR-PRESSO analysis. Leave-one-out analysis ensured result stability. Results：We detected that Cathepsin S acts as a protective factor against cardioembolic IS(IVW: p=0.014, odds ratio (OR) = 0.918, 95% confidence interval (CI) = 0.857-0.983).In the reverse causation analysis, we found a positive correlation between overall stroke and Cathepsin S (IVW: p=0.006, OR=1.509, 95%CI=1.128-2.019), IS and Cathepsin S (IVW: p=0.015, OR=1.368, 95%CI=1.063-1.762), and large artery IS and Cathepsin S (IVW: p=0.034, OR=1.225, 95%CI=1.015-1.479). Multivariable MR indicated a negative correlation between Cathepsin S and both cardioembolic IS (IVW: p=0.002, OR=0.889, 95%CI=0.825-0.958) and IS (IVW: p=0.032, OR=0.964, 95%CI=0.932-0.997), and between Cathepsin F and IS (IVW: p=0.040, OR=0.946, 95%CI=0.898-0.998). Conversely, Cathepsin E showed a positive correlation with small vessel IS (IVW: p=0.022, OR=1.155, 95%CI=1.021-1.307). Conclusion：This study provides genetic evidence that Cathepsin S may be a potential protective factor against cardioembolic IS. Further studies are required to elucidate the underlying mechanisms of this causal relationship.