Circulating interleukin-6 levels and incident ischemic stroke: a systematic review and meta-analysis of population-based cohort studies

Abstract

Objective: To determine the association between circulating interleukin-6 (IL-6) levels and risk of incident ischemic stroke in the general population. Methods: Following the PRISMA guidelines, we systematically searched the literature for population-based prospective cohort studies exploring the association between circulating IL-6 levels and risk of incident ischemic stroke. We pooled association estimates for ischemic stroke risk with random-effect meta-analyses and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). Results: We identified 11 studies (n=27,411 individuals; 2,669 incident stroke cases) meeting our eligibility criteria. Overall, quality of the included studies was high (median 8 out of 9 NOS points). In meta-analyses, 1-standard deviation increment in circulating IL-6 levels was associated with a 19% increase in risk of incident ischemic stroke over a mean follow-up of 12.4 years (RR 1.19; 95% CI 1.10 to 1.28). A dose-response meta-analysis showed a linear association between circulating IL-6 levels and ischemic stroke risk. There was only moderate heterogeneity and the results were consistent in sensitivity analyses restricted to studies of low risk of bias and studies fully adjusting for demographic and vascular risk factors. The results also remained stable following adjustment for publication bias. Conclusions: Higher circulating IL-6 levels in community-dwelling individuals are associated with higher long-term risk of incident ischemic stroke in a linear pattern and independently of conventional vascular risk factors. Along with findings from genetic studies and clinical trials, these results provide additional support for a key role of IL-6 signaling in ischemic stroke.