Journal Article

DZNE-2025-00123

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.

Konieczny, M. J. ; Omarov, M. ; Zhang, L. ; Malik, R. ; Richardson, T. G. ; Baumeister, S.-E. ; Bernhagen, J. ; Dichgans, M.DZNE* ; Georgakis, M. K.

2025
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s42003-025-07453-w

Abstract: Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of the Atypical Chemokine Receptor 1 (ACKR1) acting as scavenger for multiple chemokines and the role of tumor necrosis factor receptor-associated factor 1 (TRAFD1) in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR using 2 independent proteomics datasets paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohn's disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.

Keyword(s): Humans (MeSH) ; Cytokines: blood (MeSH) ; Cytokines: genetics (MeSH) ; Cytokines: metabolism (MeSH) ; Genome-Wide Association Study (MeSH) ; Immune System Diseases: genetics (MeSH) ; Immune System Diseases: drug therapy (MeSH) ; Immune System Diseases: blood (MeSH) ; Immune System Diseases: immunology (MeSH) ; Mendelian Randomization Analysis (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Genomics: methods (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Cytokines

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Contributing Institute(s):

1. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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