TY - JOUR
T1 - Dissecting the IL-6 pathway in cardiometabolic disease
T2 - A Mendelian randomization study on both IL6 and IL6R
AU - CHARGE Inflammation working group
AU - Cupido, Arjen J
AU - Asselbergs, Folkert W
AU - Natarajan, Pradeep
AU - Ridker, Paul M
AU - Hovingh, G Kees
AU - Schmidt, A Floriaan
N1 - © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
KW - Arthritis, Rheumatoid/drug therapy
KW - Atrial Fibrillation
KW - Coronary Artery Disease/genetics
KW - Diabetes Mellitus, Type 2/genetics
KW - Genome-Wide Association Study
KW - Humans
KW - Interleukin-6/genetics
KW - Ischemic Stroke
KW - Mendelian Randomization Analysis
KW - Polymorphism, Single Nucleotide
KW - Receptors, Interleukin-6/genetics
KW - Risk Factors
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85123935665&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34931349
U2 - https://doi.org/10.1111/bcp.15191
DO - https://doi.org/10.1111/bcp.15191
M3 - Article
C2 - 34931349
SN - 0306-5251
VL - 88
SP - 2875
EP - 2884
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
IS - 6
ER -