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Association of Protein C, but Not Protein S or Antithrombin With Ischemic Stroke: Bidirectional Two-Sample Mendelian
1Department of Neurology, Shanghai Ninth People's Hospital, Shanghai, China.
Insights
Lower protein C levels increase ischemic stroke risk, with body mass index partially mediating this effect. This suggests potential prevention strategies targeting protein C for ischemic stroke.
Area of Science:
- Cardiovascular Genetics
- Thrombosis and Hemostasis
- Epidemiology
Background:
- Ischemic stroke (IS) poses a significant health burden.
- The role of anticoagulation factors like protein C and protein S in IS risk requires further elucidation.
- Understanding genetic predispositions to IS is crucial for developing targeted interventions.
Purpose of the Study:
- To investigate the causal effects of protein C, protein S, and anti-thrombin on ischemic stroke risk using a Mendelian randomization approach.
- To explore potential mediating factors, such as body mass index (BMI), in the relationship between these anticoagulation factors and IS.
- To validate the association between protein C and IS through a systematic review and meta-analysis.
Main Methods:
- A two-sample bidirectional Mendelian randomization (MR) framework was employed using large-scale genome-wide association study data.
- Mediating analysis was performed to assess the role of risk factors, including BMI.
- A systematic review and meta-analysis of relevant literature was conducted to confirm findings.
Main Results:
- Genetic variants associated with lower protein C levels were causally linked to an increased risk of ischemic stroke (OR: 0.918; P=1.027e-05).
- No significant causal association was found for protein S or anti-thrombin with ischemic stroke risk.
- Body mass index (BMI) was identified as a partial mediator, explaining 5.88% of the effect.
- Meta-analysis of observational studies showed a significantly higher IS risk in individuals with decreased protein C (RR: 5.47).
Conclusions:
- Protein C exhibits a causal relationship with reduced ischemic stroke risk.
- Body mass index partially mediates the causal effect of protein C on ischemic stroke.
- These findings suggest that targeting protein C levels or associated factors like BMI may offer novel prevention strategies for ischemic stroke.
Abstract:
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.
