1. Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis.
- Author
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Prapiadou S, Živković L, Thorand B, George MJ, van der Laan SW, Malik R, Herder C, Koenig W, Ueland T, Kleveland O, Aukrust P, Gullestad L, Bernhagen J, Pasterkamp G, Peters A, Hingorani AD, Rosand J, Dichgans M, Anderson CD, and Georgakis MK
- Subjects
- Humans, Coronary Artery Disease genetics, Genome-Wide Association Study, Mendelian Randomization Analysis, Peripheral Arterial Disease, Proteomics, Stroke genetics, Atherosclerosis genetics, Chemokine CXCL10 metabolism, Interleukin-6 metabolism, Proteogenomics
- Abstract
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., Competing Interests: Disclosures Dr Anderson receives sponsored research support from the American Heart Association (AHA) (18SFRN3425000) and Bayer AG, and has consulted for ApoPharma, Inc. Dr Rosand receives sponsored research support from the National Institutes of Health, AHA and OneMind, and consults for Takeda Pharmaceuticals. Dr Koenig reports advisory board fees from AstraZeneca, Novartis, Amgen, Pfizer, The Medicines Company, DalCor, Kowa, Corvidia, OMEICOS, Daiichi-Sankyo, Novo Nordisk, New Amsterdam Pharma, TenSixteen Bio, Esperion, Genentech; lecture fees from Bristol-Myers Squibb, Novartis, Amgen, Berlin-Chemie, Sanofi and AstraZeneca; grants and nonfinancial support from Abbott, Roche Diagnostics, Beckmann, and Singulex, outside the submitted work. Dr Bernhagen is inventor on patent applications related to anti-MIF/chemokine strategies in inflammatory and cardiovascular diseases.
- Published
- 2024
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