The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases
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...
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Nature Portfolio
2025-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-07453-w |
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| author | Marek J. Konieczny Murad Omarov Lanyue Zhang Rainer Malik Tom G. Richardson Sebastian-Edgar Baumeister Jürgen Bernhagen Martin Dichgans Marios K. Georgakis |
| author_facet | Marek J. Konieczny Murad Omarov Lanyue Zhang Rainer Malik Tom G. Richardson Sebastian-Edgar Baumeister Jürgen Bernhagen Martin Dichgans Marios K. Georgakis |
| author_sort | Marek J. Konieczny |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-29d561c26c1a4530b92f9aa871c20c08 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-29d561c26c1a4530b92f9aa871c20c082025-01-12T12:35:48ZengNature PortfolioCommunications Biology2399-36422025-01-018111810.1038/s42003-025-07453-wThe genomic architecture of circulating cytokine levels points to drug targets for immune-related diseasesMarek J. Konieczny0Murad Omarov1Lanyue Zhang2Rainer Malik3Tom G. Richardson4Sebastian-Edgar Baumeister5Jürgen Bernhagen6Martin Dichgans7Marios K. Georgakis8Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU MunichMedical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of BristolInstitute of Health Services Research in Dentistry, University of MünsterInstitute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU MunichInstitute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU MunichAbstract 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.https://doi.org/10.1038/s42003-025-07453-w |
| spellingShingle | Marek J. Konieczny Murad Omarov Lanyue Zhang Rainer Malik Tom G. Richardson Sebastian-Edgar Baumeister Jürgen Bernhagen Martin Dichgans Marios K. Georgakis The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases Communications Biology |
| title | The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases |
| title_full | The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases |
| title_fullStr | The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases |
| title_full_unstemmed | The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases |
| title_short | The genomic architecture of circulating cytokine levels points to drug targets for immune-related diseases |
| title_sort | genomic architecture of circulating cytokine levels points to drug targets for immune related diseases |
| url | https://doi.org/10.1038/s42003-025-07453-w |
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