Causal association of inflammation with ischemic stroke and its subtypes: a bidirectional Mendelian randomization study

Background

Emerging evidence underscores a bidirectional relationship between ischemic stroke (IS) and inflammation, yet the causality of this association remains uncertain. We conducted a two-sample bidirectional Mendelian randomization (MR) study aimed at investigating the causal links between inflammation and IS.

Methods

Single nucleotide polymorphism from genome-wide association studies of 112 inflammatory cytokines and IS were chosen as instrumental variables. We evaluated the causal effects of inflammatory factors on IS outcomes and examined the mediating effects of risk factors for IS. Additionally, reverse MR analysis was conducted to determine whether the occurrence of IS influenced levels of inflammatory cytokines. Causal associations were assessed using inverse variance weighting, complemented by sensitivity analyses incorporating weighted median and MR-Egger methods.

Results

We found associations between genetically predicted plasma levels of 25 inflammatory factors and IS along with its subtypes. MR supports smoking, body mass index, atrial fibrillation, coronary artery disease, heart failure, systolic blood pressure, diastolic blood pressure and type 2 diabetes as risk factors for IS. Notably, coronary artery disease and heart failure seemed to mediate the RANTES, HGF, IL-5 associations with IS. In addition, reverse MR analysis suggested a causal relationship between IS and its subtypes and 19 inflammatory factors.

Conclusion

In summary, inflammation was suggestively causally associated with the risk of IS, and inflammatory cytokines had downstream effect on IS. Future studies should explore whether inflammatory factors found to have significant associations with IS risk could be manipulated to reduce IS risk, and the neuroinflammatory mechanisms after IS.