Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study.

Background Studies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown. Methods In a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor ( IL6R ) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R. Results We identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque. Conclusions We provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials. What is new What are the clinical implications ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement M. Georgakis was funded by scholarships from the Onassis Foundation and the German Academic Exchange Service (DAAD). D. Gill is funded by the Wellcome Trust. This project has received funding from the European Union’s Horizon 2020 research and innovation programme (No 666881), SVDs@target (to M. Dichgans) and No 667375, CoSTREAM (to M. Dichgans); the DFG as part of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy - ID 390857198) and the CRC 1123 (B3) (to M. Dichgans); the Corona Foundation (to M. Dichgans); the Fondation Leducq (Transatlantic Network of Excellence on Pathogenesis of Small Vessel Disease of the Brain, to M. Dichgans); the e:Med program (e:AtheroSysMed, to M. Dichgans) and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456, to M. Dichgans). ### Author Declarations All relevant ethical guidelines have been followed and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Not Applicable Any clinical trials involved have been registered with an ICMJE-approved registry such as ClinicalTrials.gov and the trial ID is included in the manuscript. Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant Equator, ICMJE or other checklist(s) as supplementary files, if applicable. Not Applicable All analyses presented in the manuscript have been conducted with publically available data. The instruments extracted for IL6 signaling are available in Table 1, for other authors to replicate our findings and use them in future work.