Associations of the inflammasome-dependent cytokine IL-18 with risk of coronary heart disease

Aims Inflammasome activation has emerged as a promising therapeutic target to reduce residual cardiovascular (CV) risk in patients on guideline lipid-lowering therapy. IL-1 beta and IL-6 have been intensively studied, whereas the role of the inflammasome-related cytokine IL-18 has gained less attention. Here we aimed to assess the associations of IL-18 with risk of coronary events and severity of atherosclerosis.Methods and results The study included 4742 participants participating in a prospective Swedish Malm & ouml; Diet and Cancer (MDC) cohort study, 54 219 general population participants in the UK Biobank, and 1500 participants with Type 2 diabetes and/or known CV disease in the European multicentre SUMMIT VIP imaging study. Plasma levels of IL-18 were analysed using proximity extension assay and atherosclerosis by carotid ultrasound. The incidence of MI and CV death was registered during a 23-year follow-up for the MDC cohort and for a 15-year follow-up for the UK Biobank cohort. There were 617 cases of MI and 644 CV deaths in the MDC cohort and 2454 cases of MI and 1537 CV deaths in the UK Biobank cohort. Elevated IL-18 was associated with an increased risk of MI and CV death independent of hsCRP and IL-6 in both cohorts. In Cox proportional hazards regression models, this association was independent of major CV risk factors in the UK Biobank but not in the MDC cohort. IL-18 did not provide clinically meaningful risk reclassification in the UK Biobank cohort. The association of IL-18 with carotid atherosclerosis in the SUMMIT VIP cohort was weaker than that of IL-6.Conclusion IL-18 is independently associated with risk of MI and CV death in the general population but does not improve clinical risk stratification. Targeting IL-18 directly or through inflammasome inhibition represents a promising approach for treatment of residual inflammatory risk in high-risk atherosclerosis patients that merits to be evaluated in future randomized clinical trials.