Abstract

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.

Using multi-omic data, this Mendelian Randomization study provides evidence that IL-18 lowering is associated with a lower lifetime risk of cardiac remodeling, heart failure, and cardio-embolic stroke.

A significant proportion of the protective effect of impaired IL-18 signaling on cardio-embolic stroke was mediated through a reduced risk of AF.

These data provide compelling evidence that the IL-18 signaling pathway is a promising druggable target for the treatment of heart failure and the prevention of cardio-embolic stroke.

Several monoclonal antibodies targeting IL-18 are in development for the treatment of atopic dermatitis and could be considered for re-purposing for cardiovascular disease.

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.

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AbbreviationsHFHeart failureNLRPNOD-like receptor family pyrin domain-containingAFAtrial fibrillationIL-18Interleukin-18CMRCardiac magnetic resonanceCRPC-reactive proteinIFN-γInterferon-gammaCVDcardiovascular diseaseMRMendelian randomizationGWASGenome-wide association study