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Prapiadou, S.* ; Živković, L.* ; Thorand, B. ; George, M.J.* ; van der Laan, S.W.* ; Malik, R.* ; Herder, C.* ; Koenig, W.* ; Ueland, T.* ; Kleveland, O.* ; Aukrust, P.* ; Gullestad, L.* ; Bernhagen, J.* ; Pasterkamp, G.* ; Peters, A. ; Hingorani, A.D.* ; Rosand, J.* ; Dichgans, M.* ; Anderson, C.D.* ; Georgakis, M.K.*

Proteogenomic data integration reveals CXCL10 as a potentially downstream causal mediator for IL-6 signaling on atherosclerosis.

Circulation 149, 669-683 (2024)
Postprint DOI PMC
Open Access Green
Free by publisher: Publ. Version/Full Text online available 01/2025
BACKGROUND: Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects. METHODS: Leveraging data from 522 681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6R (IL-6 receptor) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization, we assessed its effects on 3281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3301). Using mediation Mendelian randomization, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions. RESULTS: We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 (C-X-C motif chemokine ligand 10) were associated with risk of coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease, with up to 67% of the effects of genetically downregulated IL-6 signaling on these end points mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher CXCL10 expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling. CONCLUSIONS: Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ-inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in 3 vascular compartments and, as such, could serve as a promising drug target for atheroprotection.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Mendelian Randomization Analysis ; Atherosclerosis ; Interleukin-6; Coronary-heart-disease; Mendelian Randomization; Interleukin-6 Receptor; Monica/kora Augsburg; Risk; Atherogenesis; Inflammation; Loci
ISSN (print) / ISBN 0009-7322
e-ISSN 1524-4539
Journal Circulation
Quellenangaben Volume: 149, Issue: 9, Pages: 669-683 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Grants State of Bavaria
Leducq Foundation
German Research Foundation (DFG)
Hertie Foundation
Fritz-Thyssen Foundation
European Union
ERA-NET Neuron
National Institutes of Health
Helmholtz Zentrum Munchen - German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF)
DFG
German Federal Ministry of Education and Research (BMBF) through the German Center for Diabetes Research (DZD)
Ministry of Culture and Science of the state North Rhine-Westphalia (Dusseldorf, Germany)
German Federal Ministry of Health (Berlin, Germany)
MGH McCance Center for Brain Health
AHA-Bugher
American Heart Association (AHA)
German Research Foundation (Deutsche Forschungsgemeinschaft