Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study

Abstract

ObjectivesPrevious observational studies have indicated correlations between various inflammatory cytokines and functional outcomes following ischemic stroke (IS); however, the causality remains unclear. We aimed to further evaluate the causal association between 41 circulating inflammatory cytokines and functional outcomes following IS.MethodsTwo‐sample bidirectional Mendelian randomization (MR) analysis was used in this study. The genetic variation of 41 circulating inflammatory cytokines were derived from genome‐wide association study (GWAS) data of European ancestry (n = 8293). The corresponding genetic association of functional outcomes following IS were derived from European ancestry GWAS data (n = 6021).ResultsInverse variance weighted (IVW) analysis showed that genetically predicted increased levels of regulation and activation in normal T‐cell expression and secretion factor (RANTES/CCL5) and eosinophilic chemotactic factor (EOTAXIN/CCL11) were positively correlated with the increased adverse functional outcomes (modified Rankin Scale [mRS≥3] following IS (OR: 1.40, 95% CI: 1.002–1.96, p = 0.049; OR: 1.33, 95% CI: 1.15–1.54, p = 0.0001). Interleukin 18 (IL‐18) level might be the downstream consequence of adverse functional outcomes following IS (β: −0.09, p = 0.039). Other inflammatory cytokines and functional outcomes following IS did not appear to be causally related.ConclusionsThis study suggests a causality between inflammation and adverse functional outcomes following IS. RANTES (CCL5) and EOTAXIN (CCL11) may be the upstream factors of adverse functional outcomes following IS, while IL‐18 may be the downstream effect of adverse functional outcomes following IS. Whether these cytokines can be used to predict or improve adverse functional outcomes after IS requires further researches.

Evaluation of a pleiotropic cytokinin polymorphism with cerebral infarction in a Chinese male population

“…Genetic variations in genes encoding cytokines and their receptors have been implicated in the susceptibility to stroke and its subtypes [5]. Polymorphisms in cytokine genes can influence the production, secretion, and activity of cytokines, leading to altered immune responses and inflammatory processes.…”

“…Studies investigating the association between IL-6 polymorphisms and stroke risk have yielded inconsistent results, with some studies reporting a positive correlation between specific IL-6 genotypes and stroke susceptibility, while others have failed to replicate these findings [5]. The relationship between IL-6 polymorphisms and stroke risk may be influenced by various factors, including the ethnic background of the study population, sample size, study design, and adjustment for confounding variables [6].…”