{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:08:41Z","timestamp":1791299321113,"version":"4.1.0"},"reference-count":66,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,2,27]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>Leveraging data from 522\u2009681 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              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\n              <jats:italic toggle=\"yes\">CXCL10<\/jats:italic>\n              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.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>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-\u03b3\u2013inducible 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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.123.064974","type":"journal-article","created":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T10:00:24Z","timestamp":1703757624000},"page":"669-683","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":60,"title":["Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis"],"prefix":"10.1161","volume":"149","author":[{"given":"Savvina","family":"Prapiadou","sequence":"first","affiliation":[{"name":"University of Patras School of Medicine, Greece (S.P.)."},{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston (S.P., J.R., 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J.","family":"George","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Division of Medicine, University College London, United Kingdom (M.J.G., A.D.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6888-1404","authenticated-orcid":true,"given":"Sander W.","family":"van der Laan","sequence":"additional","affiliation":[{"name":"Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, The Netherlands (S.W.v.d.L., G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-2520","authenticated-orcid":true,"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[{"name":"Institute for Stroke and Dementia Research, Ludwig-Maximilians-University of Munich, Germany (L.Z., R.M., J.B., M.D., 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of Epidemiology and Medical Biometry, University of Ulm, Germany (W.K.)."},{"name":"German Heart Center Munich, Technical University of Munich, Germany (W.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5005-0784","authenticated-orcid":true,"given":"Thor","family":"Ueland","sequence":"additional","affiliation":[{"name":"Thrombosis Research Center (TREC), Division of internal medicine, University hospital of North Norway, Troms\u00f8 (T.U.)."},{"name":"Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Norway (T.U., P.A.)."},{"name":"Institute of Clinical Medicine, University of Oslo, Norway (T.U., P.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ola","family":"Kleveland","sequence":"additional","affiliation":[{"name":"Clinic of Cardiology, St Olavs Hospital, Trondheim, Norway (O.K.)."},{"name":"Department of Circulation and Medical Imaging, Norwegian University of Science and 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Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Germany (W.K., J.B., M.D.)."},{"name":"Munich Cluster for Systems Neurology (SyNergy), Germany (J.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5345-1022","authenticated-orcid":true,"given":"Gerard","family":"Pasterkamp","sequence":"additional","affiliation":[{"name":"Central Diagnostics Laboratory, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, The Netherlands (S.W.v.d.L., G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6645-0985","authenticated-orcid":true,"given":"Annette","family":"Peters","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology, Helmholtz Zentrum M\u00fcnchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany (B.T., A.P.)."},{"name":"Chair of Epidemiology, Institute for Medical Information 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