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

孟德尔随机化 生物 免疫系统 信号转导 转录组 人口 细胞因子 免疫学 疾病 生物信息学 医学 基因 内科学 遗传学 基因表达 遗传变异 基因型 环境卫生
作者
Savvina Prapiadou,Luka Živković,Barbara Thorand,Marc J. George,Sander W. van der Laan,Rainer Malik,Christian Herder,Wolfgang Köenig,Thor Ueland,Ola Kleveland,Pål Aukrust,Lars Gullestad,Jürgen Bernhagen,Gerard Pasterkamp,Annette Peters,Aroon D. Hingorani,Jonathan Rosand,Martin Dichgans,Christopher D. Anderson,Marios K. Georgakis
出处
期刊:Cold Spring Harbor Laboratory - medRxiv
标识
DOI:10.1101/2023.03.24.23287543
摘要

ABSTRACT Background Genetic and experimental studies support a causal involvement of interleukin-6 (IL-6) signaling in atheroprogression. While 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-6 receptor (IL-6R) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization (MR), we assessed its effects on 3,281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3,301). Using mediation MR, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease (CAD), large artery atherosclerotic stroke (LAAS), and peripheral artery disease (PAD). For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1,704) 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 were associated with risk of CAD, LAAS, and PAD with up to 67% of the effects of genetically downregulated IL-6 signaling on these endpoints 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 three vascular compartments and as such could serve as a promising drug target for atheroprotection.
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