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Papadopoulos, A.* ; Palaiopanos, K.* ; Björkbacka, H.* ; Peters, A. ; de Lemos, J.A.* ; Seshadri, S.* ; Dichgans, M.* ; Georgakis, M.K.*

Circulating interleukin-6 levels and incident ischemic stroke: A systematic review and meta-analysis of prospective studies

Neurology 98, e1002-e1012 (2022)
Postprint DOI PMC
Open Access Green
BACKGROUND AND OBJECTIVES: Human genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. Still, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. Here, we set out to perform a systematic review and meta-analysis of aggregate data on cohort studies to determine the magnitude and shape of the association between circulating IL-6 levels and risk of incident ischemic stroke in the general population. METHODS: Following the PRISMA guidelines, we systematically screened the PubMed search engine from inception to March 2021 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-effects models and explored non-linear effects in dose-response meta-analyses. Risk of bias was assessed with the Newcastle-Ottawa scale (NOS). We used funnel plots and trim-to-fill analyses to assess publication bias. RESULTS: We identified 11 studies (n=27,411 individuals; 2,669 stroke events) meeting our eligibility criteria. Mean age of all included participants was 60.5 years and 54.8% were females. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7 to 9). In meta-analyses, 1-standard deviation increment in circulating log-transformed 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. DISCUSSION: 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Coronary-heart-disease; C-reactive Protein; Inflammatory Cytokines; Risk-factors; Mortality; Events; Bias; Atherosclerosis; Associations; Publication
ISSN (print) / ISBN 0028-3878
e-ISSN 1526-632X
Journal Neurology
Quellenangaben Volume: 98, Issue: 10, Pages: e1002-e1012 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Grants FoFoLe program of LMU Munich
Swedish Heart-Lung Foundation
NHLBI
NINDS
Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy
Walter-Benjamin fellowship from the German Research Foundation (DFG)
Onassis Foundation
German Academic Exchang Service
Vascular Dmentia Research Foundation
Swedish Research Council