RT Journal Article
SR Electronic
T1 Circulating Interleukin-6 Levels and Incident Ischemic Stroke
JF Neurology
JO Neurology
FD Lippincott Williams & Wilkins
SP e1002
OP e1012
DO 10.1212/WNL.0000000000013274
VO 98
IS 10
A1 Papadopoulos, Andreas
A1 Palaiopanos, Konstantinos
A1 Björkbacka, Harry
A1 Peters, Annette
A1 de Lemos, James A.
A1 Seshadri, Sudha
A1 Dichgans, Martin
A1 Georgakis, Marios K.
YR 2022
UL http://n.neurology.org/content/98/10/e1002.abstract
AB 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.CI=confidence interval; CRP=C-reactive protein; HDL=high-density lipoprotein; HR=hazard ratio; IL-6=interleukin-6; NOS=Newcastle-Ottawa Scale; RCT=randomized clinical trial; RR=relative risk