Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis
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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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:149 |
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| Enthalten in: |
Circulation - 149(2024), 9 vom: 27. Feb., Seite 669-683 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Prapiadou, Savvina [VerfasserIn] |
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| Links: |
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| Themen: |
Atherosclerosis |
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| Anmerkungen: |
Date Completed 28.02.2024 Date Revised 03.04.2024 published: Print-Electronic UpdateOf: medRxiv. 2023 Mar 28;:. - PMID 37034659 Citation Status MEDLINE |
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| doi: |
10.1161/CIRCULATIONAHA.123.064974 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis |
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| 500 | |a Date Revised 03.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a UpdateOf: medRxiv. 2023 Mar 28;:. - PMID 37034659 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Mendelian randomization analysis | |
| 650 | 4 | |a atherosclerosis | |
| 650 | 4 | |a interleukin-6 | |
| 650 | 7 | |a Chemokine CXCL10 |2 NLM | |
| 650 | 7 | |a CXCL10 protein, human |2 NLM | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 700 | 1 | |a Živković, Luka |e verfasserin |4 aut | |
| 700 | 1 | |a Thorand, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a George, Marc J |e verfasserin |4 aut | |
| 700 | 1 | |a van der Laan, Sander W |e verfasserin |4 aut | |
| 700 | 1 | |a Malik, Rainer |e verfasserin |4 aut | |
| 700 | 1 | |a Herder, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Koenig, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Ueland, Thor |e verfasserin |4 aut | |
| 700 | 1 | |a Kleveland, Ola |e verfasserin |4 aut | |
| 700 | 1 | |a Aukrust, Pål |e verfasserin |4 aut | |
| 700 | 1 | |a Gullestad, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Bernhagen, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Pasterkamp, Gerard |e verfasserin |4 aut | |
| 700 | 1 | |a Peters, Annette |e verfasserin |4 aut | |
| 700 | 1 | |a Hingorani, Aroon D |e verfasserin |4 aut | |
| 700 | 1 | |a Rosand, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Dichgans, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Christopher D |e verfasserin |4 aut | |
| 700 | 1 | |a Georgakis, Marios K |e verfasserin |4 aut | |
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