Dissecting the IL‐6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R

AIMS: Chronic inflammation is a risk factor for cardiovascular disease (CVD). IL‐6 signalling perturbation through IL‐6 or IL‐6R blockade may have potential benefit on cardiovascular risk. It is unknown whether targeting either IL‐6 or IL‐6 receptor may result in similar effects on CVD and adverse events. We compared the anticipated effects of targeting IL‐6 and IL‐6 receptor on cardiometabolic risk and potential side effects. METHODS: We constructed four instruments: two main instruments with genetic variants in the IL6 and IL6R loci weighted for their association with CRP, and two after firstly filtering variants for their association with IL‐6 or IL‐6R expression. Analyses were performed for coronary artery disease (CAD), ischemic stroke, atrial fibrillation (AF), heart failure, type 2 diabetes (T2D), rheumatoid arthritis (RA), infection endpoints, and quantitative haematological, metabolic and anthropometric parameters. RESULTS: A 1 mg/L lower CRP by the IL6 instrument was associated with lower CAD (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.77;0.96), AF and T2D risk. A 1 mg/L lower CRP by the IL6R instrument was associated with lower CAD (OR 0.90, 95% CI 0.86;0.95), any stroke and ischemic stroke, AF, RA risk and higher pneumonia risk. The eQTL‐filtered results were in concordance with the main results, but with wider confidence intervals. CONCLUSIONS: IL‐6 signalling perturbation by either IL6 or IL6R genetic instruments is associated with a similar risk reduction for multiple cardiometabolic diseases, suggesting that both IL‐6 and IL‐6R are potential therapeutic targets to lower CVD. Moreover, IL‐6 rather than IL‐6R inhibition might have a more favourable pneumonia risk.