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024 7 _ |a 10.1038/s42003-025-07453-w
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037 _ _ |a DZNE-2025-00123
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100 1 _ |a Konieczny, Marek J
|0 0000-0003-3592-7191
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245 _ _ |a The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.
260 _ _ |a London
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|b Springer Nature
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520 _ _ |a 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.
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650 _ 7 |a Cytokines
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Cytokines: blood
|2 MeSH
650 _ 2 |a Cytokines: genetics
|2 MeSH
650 _ 2 |a Cytokines: metabolism
|2 MeSH
650 _ 2 |a Genome-Wide Association Study
|2 MeSH
650 _ 2 |a Immune System Diseases: genetics
|2 MeSH
650 _ 2 |a Immune System Diseases: drug therapy
|2 MeSH
650 _ 2 |a Immune System Diseases: blood
|2 MeSH
650 _ 2 |a Immune System Diseases: immunology
|2 MeSH
650 _ 2 |a Mendelian Randomization Analysis
|2 MeSH
650 _ 2 |a Polymorphism, Single Nucleotide
|2 MeSH
650 _ 2 |a Genomics: methods
|2 MeSH
650 _ 2 |a Genetic Predisposition to Disease
|2 MeSH
700 1 _ |a Omarov, Murad
|0 0000-0001-6126-8631
|b 1
700 1 _ |a Zhang, Lanyue
|b 2
700 1 _ |a Malik, Rainer
|b 3
700 1 _ |a Richardson, Tom G
|0 0000-0002-7918-2040
|b 4
700 1 _ |a Baumeister, Sebastian-Edgar
|b 5
700 1 _ |a Bernhagen, Jürgen
|0 0000-0003-2996-2652
|b 6
700 1 _ |a Dichgans, Martin
|0 P:(DE-2719)2000030
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700 1 _ |a Georgakis, Marios K
|0 0000-0003-3507-3659
|b 8
773 _ _ |a 10.1038/s42003-025-07453-w
|g Vol. 8, no. 1, p. 34
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|t Communications biology
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|y 2025
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856 4 _ |u https://pub.dzne.de/record/275888/files/DZNE-2025-00123%20SUP.zip
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