Genetically Predicted IL-18 Inhibition and Risk of Cardiovascular Events: A Mendelian Randomization Study

Background: Inflammation is an emerging target for the prevention and treatment of cardiovascular disease (CVD). This drug-target Mendelian randomization (MR) study aimed to predict the on-target effects of IL-18 inhibition on CVD risk. Furthermore, we aimed to explore the effects of IL-18 inhibition on cardio-metabolic traits, cardiac structure and function, and identify potential adverse outcomes. Methods: We selected five independent circulating IL-18-lowering variants around the IL-18 gene locus from the Systematic and Combined AnaLysis of Olink Proteins (SCALLOP) consortium. We then performed two-sample MR analyses to investigate the association of genetically proxied IL-18-inhibition on downstream inflammatory markers, risk of CVD, cardiac magnetic resonance (CMR) imaging measurements of cardiac structure and function, cardiometabolic traits, and a selection of potential adverse effects. We utilized data from the UK Biobank, Cardiogram, GIGASTROKE, and other large genomic consortia (sample range: 3,301-1,320,016). Results: Following correction for multiple comparisons, one standard deviation (SD) lower in genetically-predicted circulating IL-18 was associated with reductions in downstream biomarkers of IL-18 signaling, including C-reactive protein (SD change -0.02, 95% CI -0.03, -0.02), tumor necrosis factor (SD change -0.19, CI -0.25, -0.14), interferon-gamma (SD change -0.15, CI -0.22, -0.08), and CXCL10 (SD change -0.13, CI -0.16, -0.09). Lower genetically-predicted IL-18 levels were associated with reduced risk of cardio-embolic stroke (Odds Ratio [OR] 0.85, CI 0.79-0.92), but not other stroke subtypes. Furthermore, lower genetically predicted IL-18 levels were associated with reduced risk of peripheral arterial disease (OR 0.91, CI 0.84-0.97), atrial fibrillation (OR 0.94, CI 0.89-0.99), and heart failure (OR 0.84, CI 0.77-0.92), as well as improvements in CMR traits, including a reduction in left atrial volume (β -0.02, CI -0.03, -0.00). Lower genetically-predicted IL-18 levels were associated with lower risk of chronic kidney disease, autoimmune diseases, a favorable cardio-metabolic profile, and higher odds of lung cancer, but not infections. Conclusions: Our study provides genetic support that impaired IL-18 signaling may be causally associated with a lower risk of cardio-embolic stroke, possibly mediated through prevention of cardiac re-modelling, heart failure and atrial fibrillation. IL-18 represents a potential target for anti-inflammatory therapy in stroke and CVD that warrants further investigation in clinical trials. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement PJK has received funding from the Irish Health Research Board. DG is supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College London. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: N/A I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This study utilizes publicly available, summary-level GWAS data that can be accessed through the GWAS Catalogue (https://www.ebi.ac.uk/gwas/home) and the Integrative Epidemiology Unit (IEU) OpenGWAS project (https://gwas.mrcieu.ac.uk/) or specific cohort portals, including The Scallop Consortium (https://zenodo.org/records/2615265), The Centre for Statistical Genetics (https://csg.sph.umich.edu/willer/public/afib2018/), Pan-UK Biobank (https://pan.ukbb.broadinstitute.org/), The Human Genetics Amplifier (HuGeAMP) (https://kp4cd.org/node/169), The Usher Institute of Population Health Sciences and Informatics (https://datashare.ed.ac.uk/handle/10283/3209), The Cardiovascular Disease Knowledge Portal (https://cvd.hugeamp.org/downloads.html), The NBDC Human Database (https://humandbs.dbcls.jp/en/), The Complex Trait Genetics Lab (https://cncr.nl/research/summary\_statistics/) and FinnGen (https://www.finngen.fi/en/access\_results).