Journal
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Volume 88, Issue 6, Pages 2875-2884Publisher
WILEY
DOI: 10.1111/bcp.15191
Keywords
cardiovascular disease; classical signalling; IL-6; trans-signalling
Categories
Funding
- Atheros fund
- AMC Young Talent Fund
- UCL Hospitals NIHR Biomedical Research Centre
- National Heart, Lung, and Blood Institute [R01HL142711, R01HL148565, R01HL148050, R01HL151283]
- Fondation Leducq [TNE-18CVD04]
- Hassenfeld Scholar Award from the Massachusetts General Hospital
- Kowa
- Novartis
- Pfizer
- AstraZeneca
- NHLBI
- NCI
- Netherlands Organization for Scientific Research
- Klinkerpad fonds
- European Union
- BHF [PG/18/5033837]
- UCL BHF Research Accelerator [AA/18/6/34223]
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Targeting IL-6 and IL-6 receptor can reduce the risk of multiple cardiometabolic diseases, suggesting both IL-6 and IL-6R are potential therapeutic targets for lowering CVD. Furthermore, IL-6 inhibition may have a more favorable effect on pneumonia risk than IL-6R inhibition.
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.
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