Association of Protein C, but Not Protein S or Antithrombin With Ischemic Stroke: Bidirectional Two-Sample Mendelian Randomization and Meta-Analysis.

AimTo explore the causal effects of protein C and protein S on ischemic stroke (IS) risk.MethodsEmploying a two-sample bidirectional Mendelian randomization (MR) framework, we investigated the causal association between protein C, protein S and anti-thrombin with ischemic stroke and further performed the mediating analysis based on several risk factors for IS. Then, systematic review and meta-analysis of relevant literature was conducted to validate the association between protein C and ischemic stroke.ResultsGenetic data from a genome-wide association study involving 440,328 individuals, including 34,217 IS patients and 406,111 controls, revealed odds ratios for IS per standard deviation (SD) increases of 0.918 (95% CI: 0.884-0.954; P=1.027e-05) for protein C, 0.997 (95% CI: 0.986-1.035; P=1.027e-05) for protein S, and 0.990 (95% CI: 0.895-1.094; P=8.383e-01) for anti-thrombin (three anticoagulation factor). Mediation analysis indicated that body mass index (BMI) partially mediated this effect, with a mediated proportion of 5.88% (95% CI, 2.236% to 7.232%). In the meta-analysis of 2107 IS patients and 12209 healthy controls, we found that patients with decreased protein C had a significantly higher risk of IS compared with controls (risk ratio: 5.47; 95% CI 3.33, 9.00).ConclusionThese findings suggest a potential relationship between protein C and ischemic stroke and BMI mediates this causal relationship, which might offer prevention strategies targeting protein C and ischemic stroke.