TY  - JOUR
AU  - Konieczny, Marek J
AU  - Omarov, Murad
AU  - Zhang, Lanyue
AU  - Malik, Rainer
AU  - Richardson, Tom G
AU  - Baumeister, Sebastian-Edgar
AU  - Bernhagen, Jürgen
AU  - Dichgans, Martin
AU  - Georgakis, Marios K
TI  - The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.
JO  - Communications biology
VL  - 8
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2025-00123
SP  - 34
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Cytokines: blood
KW  - Cytokines: genetics
KW  - Cytokines: metabolism
KW  - Genome-Wide Association Study
KW  - Immune System Diseases: genetics
KW  - Immune System Diseases: drug therapy
KW  - Immune System Diseases: blood
KW  - Immune System Diseases: immunology
KW  - Mendelian Randomization Analysis
KW  - Polymorphism, Single Nucleotide
KW  - Genomics: methods
KW  - Genetic Predisposition to Disease
KW  - Cytokines (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39794498
C2  - pmc:PMC11724035
DO  - DOI:10.1038/s42003-025-07453-w
UR  - https://pub.dzne.de/record/275888
ER  -