Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R
CHARGE Inflammation Working Group
(2022) British Journal of Clinical Pharmacology, volume 88, issue 6, pp. 2875 - 2884
(Article)
Abstract
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
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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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Keywords: IL-6, cardiovascular disease, classical signalling, trans-signalling, Receptors, Interleukin-6/genetics, Genome-Wide Association Study, Humans, Risk Factors, Arthritis, Rheumatoid/drug therapy, Diabetes Mellitus, Type 2/genetics, Ischemic Stroke, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Atrial Fibrillation, Coronary Artery Disease/genetics, Interleukin-6/genetics, Pharmacology (medical), Pharmacology, Journal Article
ISSN: 0306-5251
Publisher: Wiley-Blackwell
Note: Funding Information: A.J.C. is supported by grants from the Atheros fund and the AMC Young Talent Fund. F.W.A. is supported by UCL Hospitals NIHR Biomedical Research Centre. P.N. is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148565, R01HL148050, R01HL151283), Fondation Leducq (TNE‐18CVD04), and Hassenfeld Scholar Award from the Massachusetts General Hospital. P.M.R. has received investigator‐initiated research grants from Kowa, Novartis, Pfizer, AstraZeneca, NHLBI and NCI. G.K.H. is supported by grants from Netherlands Organization for Scientific Research, grants from Klinkerpad fonds, and grants from the European Union. A.F.S. is supported by BHF grant PG/18/5033837 and the UCL BHF Research Accelerator AA/18/6/34223. Funding Information: A.J.C. has nothing to disclose. F.W.A. and A.F.S. have received Servier funding for unrelated work. P.N. has received research support from Apple, Amgen and Boston Scientific, personal fees from Apple, Genentech, Novartis and Blackstone Life Sciences, and spousal employment at Vertex, all unrelated to the present work. P.M.R. has served as a consultant to Flame, Agepha, Corvidia, Inflammazome, Novartis, Amgen, Merck and Civi Bio and is listed as co‐inventor on patents related to the use of inflammatory biomarkers in CVD and diabetes that are no longer active. G.K.H. has received funding from Regeneron, Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Kowa, Pfizer, Regeneron Pharmaceuticals, Roche, Sanofi, The Medicines Company, Ionis and personal fees from Novo Nordisk. Publisher Copyright: © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
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