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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets.
Zhao, Jing Hua; Stacey, David; Eriksson, Niclas; Macdonald-Dunlop, Erin; Hedman, Åsa K; Kalnapenkis, Anette; Enroth, Stefan; Cozzetto, Domenico; Digby-Bell, Jonathan; Marten, Jonathan; Folkersen, Lasse; Herder, Christian; Jonsson, Lina; Bergen, Sarah E; Gieger, Christian; Needham, Elise J; Surendran, Praveen; Paul, Dirk S; Polasek, Ozren; Thorand, Barbara; Grallert, Harald; Roden, Michael; Võsa, Urmo; Esko, Tonu; Hayward, Caroline; Johansson, Åsa; Gyllensten, Ulf; Powell, Nick; Hansson, Oskar; Mattsson-Carlgren, Niklas; Joshi, Peter K; Danesh, John; Padyukov, Leonid; Klareskog, Lars; Landén, Mikael; Wilson, James F; Siegbahn, Agneta; Wallentin, Lars; Mälarstig, Anders; Butterworth, Adam S; Peters, James E.
Affiliation
  • Zhao JH; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Stacey D; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
  • Eriksson N; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Macdonald-Dunlop E; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
  • Hedman ÅK; Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
  • Kalnapenkis A; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
  • Enroth S; Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
  • Cozzetto D; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
  • Digby-Bell J; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Marten J; Development and Medical, Pfizer Worldwide Research, Stockholm, Sweden.
  • Folkersen L; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Herder C; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Jonsson L; Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala, Sweden.
  • Bergen SE; Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
  • Gieger C; School of Immunology and Microbial Sciences, King's College London, London, UK.
  • Needham EJ; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Surendran P; Nucleus Genomics ltd, New York, NY, USA.
  • Paul DS; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
  • Polasek O; German Center for Diabetes Research, Munich-Neuherberg, Germany.
  • Thorand B; Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
  • Grallert H; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
  • Roden M; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Võsa U; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Esko T; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Hayward C; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
  • Johansson Å; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Gyllensten U; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
  • Powell N; Health Data Research UK, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.
  • Mattsson-Carlgren N; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Joshi PK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
  • Danesh J; British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
  • Padyukov L; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • Klareskog L; Medical School, University of Split, Split, Croatia.
  • Landén M; German Center for Diabetes Research, Munich-Neuherberg, Germany.
  • Wilson JF; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Siegbahn A; German Center for Diabetes Research, Munich-Neuherberg, Germany.
  • Wallentin L; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Mälarstig A; Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Butterworth AS; Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
  • Peters JE; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Nat Immunol ; 24(9): 1540-1551, 2023 09.
Article in En | MEDLINE | ID: mdl-37563310
ABSTRACT
Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Inflammatory Bowel Diseases / Colitis, Ulcerative / Multiple Sclerosis Type of study: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2023 Document type: Article Affiliation country: United kingdom
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Inflammatory Bowel Diseases / Colitis, Ulcerative / Multiple Sclerosis Type of study: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Limits: Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2023 Document type: Article Affiliation country: United kingdom