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000275888 1001_ $$00000-0003-3592-7191$$aKonieczny, Marek J$$b0
000275888 245__ $$aThe genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases.
000275888 260__ $$aLondon$$bSpringer Nature$$c2025
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000275888 520__ $$aCirculating 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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000275888 650_7 $$2NLM Chemicals$$aCytokines
000275888 650_2 $$2MeSH$$aHumans
000275888 650_2 $$2MeSH$$aCytokines: blood
000275888 650_2 $$2MeSH$$aCytokines: genetics
000275888 650_2 $$2MeSH$$aCytokines: metabolism
000275888 650_2 $$2MeSH$$aGenome-Wide Association Study
000275888 650_2 $$2MeSH$$aImmune System Diseases: genetics
000275888 650_2 $$2MeSH$$aImmune System Diseases: drug therapy
000275888 650_2 $$2MeSH$$aImmune System Diseases: blood
000275888 650_2 $$2MeSH$$aImmune System Diseases: immunology
000275888 650_2 $$2MeSH$$aMendelian Randomization Analysis
000275888 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide
000275888 650_2 $$2MeSH$$aGenomics: methods
000275888 650_2 $$2MeSH$$aGenetic Predisposition to Disease
000275888 7001_ $$00000-0001-6126-8631$$aOmarov, Murad$$b1
000275888 7001_ $$aZhang, Lanyue$$b2
000275888 7001_ $$aMalik, Rainer$$b3
000275888 7001_ $$00000-0002-7918-2040$$aRichardson, Tom G$$b4
000275888 7001_ $$aBaumeister, Sebastian-Edgar$$b5
000275888 7001_ $$00000-0003-2996-2652$$aBernhagen, Jürgen$$b6
000275888 7001_ $$0P:(DE-2719)2000030$$aDichgans, Martin$$b7
000275888 7001_ $$00000-0003-3507-3659$$aGeorgakis, Marios K$$b8
000275888 773__ $$0PERI:(DE-600)2919698-X$$a10.1038/s42003-025-07453-w$$gVol. 8, no. 1, p. 34$$n1$$p34$$tCommunications biology$$v8$$x2399-3642$$y2025
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