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@ARTICLE{Konieczny:275888,
      author       = {Konieczny, Marek J and Omarov, Murad and Zhang, Lanyue and
                      Malik, Rainer and Richardson, Tom G and Baumeister,
                      Sebastian-Edgar and Bernhagen, Jürgen and Dichgans, Martin
                      and Georgakis, Marios K},
      title        = {{T}he genomic architecture of circulating cytokine levels
                      points to drug targets for immune-related diseases.},
      journal      = {Communications biology},
      volume       = {8},
      number       = {1},
      issn         = {2399-3642},
      address      = {London},
      publisher    = {Springer Nature},
      reportid     = {DZNE-2025-00123},
      pages        = {34},
      year         = {2025},
      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.},
      keywords     = {Humans / Cytokines: blood / Cytokines: genetics /
                      Cytokines: metabolism / Genome-Wide Association Study /
                      Immune System Diseases: genetics / Immune System Diseases:
                      drug therapy / Immune System Diseases: blood / Immune System
                      Diseases: immunology / Mendelian Randomization Analysis /
                      Polymorphism, Single Nucleotide / Genomics: methods /
                      Genetic Predisposition to Disease / Cytokines (NLM
                      Chemicals)},
      cin          = {AG Dichgans},
      ddc          = {570},
      cid          = {I:(DE-2719)5000022},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39794498},
      pmc          = {pmc:PMC11724035},
      doi          = {10.1038/s42003-025-07453-w},
      url          = {https://pub.dzne.de/record/275888},
}