%0 Journal Article
%A Konieczny, Marek J
%A Omarov, Murad
%A Zhang, Lanyue
%A Malik, Rainer
%A Richardson, Tom G
%A Baumeister, Sebastian-Edgar
%A Bernhagen, Jürgen
%A Dichgans, Martin
%A Georgakis, Marios K
%T The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.
%J Communications biology
%V 8
%N 1
%@ 2399-3642
%C London
%I Springer Nature
%M DZNE-2025-00123
%P 34
%D 2025
%X 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.
%K Humans
%K Cytokines: blood
%K Cytokines: genetics
%K Cytokines: metabolism
%K Genome-Wide Association Study
%K Immune System Diseases: genetics
%K Immune System Diseases: drug therapy
%K Immune System Diseases: blood
%K Immune System Diseases: immunology
%K Mendelian Randomization Analysis
%K Polymorphism, Single Nucleotide
%K Genomics: methods
%K Genetic Predisposition to Disease
%K Cytokines (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39794498
%2 pmc:PMC11724035
%R 10.1038/s42003-025-07453-w
%U https://pub.dzne.de/record/275888