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Circulating Interleukin-6 Levels and Incident Ischemic Stroke: A Systematic Review and Meta-analysis of Prospective
Andreas Papadopoulos1, Konstantinos Palaiopanos1, Harry Björkbacka1
1From the Department of Radiology (A.P.), 401 General Military Hospital of Athens; National Public Health Organization (K.P.), Athens, Greece; Department of Clinical Sciences Malmö (H.B.), Lund University, Sweden; Institute of Epidemiology (A.P.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; German Center for Diabetes Research (DZD) (A.P.), München-Neuherberg, Neuherberg; German Research Center for Cardiovascular Disease (DZHK) (A.P.), Partner Site Munich Heart Alliance; Institute of Medical Information Sciences, Biometry and Epidemiology (A.P.), and Institute for Stroke and Dementia Research, University Hospital (M.D., M.K.G.), Ludwig-Maximilians-University, Munich, Germany; Division of Cardiology (J.A.d.L.), University of Texas Southwestern Medical Center, Dallas; National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study (S.S.), Framingham; Department of Medicine (S.S.), Boston University School of Medicine, MA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases (S.S.), University of Texas Health Sciences Center, San Antonio; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany. M.K.G. is currently at the Center for Genomic Medicine, Massachusetts General Hospital, Boston and the Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.
Background And Objectives:
Human genetic studies support a key role of interleukin-6 (IL-6) in the pathogenesis of ischemic stroke. However, there are only limited data from observational studies exploring circulating IL-6 levels as a risk factor for ischemic stroke. 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 nonlinear 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 female. Overall, quality of the included studies was high (median 8 out of 9 NOS points, interquartile range 7-9). In meta-analyses, 1 SD 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 (relative risk 1.19; 95% confidence interval 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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