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.

Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.

Details

Title
Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
Author
Zhao, Jing Hua 1 ; Stacey, David 2 ; Eriksson, Niclas 3   VIAFID ORCID Logo  ; Macdonald-Dunlop, Erin 4   VIAFID ORCID Logo  ; Hedman, Åsa K. 5 ; Kalnapenkis, Anette 6 ; Enroth, Stefan 7   VIAFID ORCID Logo  ; Cozzetto, Domenico 8   VIAFID ORCID Logo  ; Digby-Bell, Jonathan 9 ; Marten, Jonathan 10 ; Folkersen, Lasse 11   VIAFID ORCID Logo  ; Herder, Christian 12   VIAFID ORCID Logo  ; Jonsson, Lina 13 ; Bergen, Sarah E. 14 ; Gieger, Christian 15   VIAFID ORCID Logo  ; Needham, Elise J. 1 ; Surendran, Praveen 16 ; Metspalu, Andres 17 ; Milani, Lili 17 ; Mägi, Reedik 17 ; Nelis, Mari 17 ; Hudjašov, Georgi 17 ; Paul, Dirk S. 18   VIAFID ORCID Logo  ; Polasek, Ozren 19 ; Thorand, Barbara 20   VIAFID ORCID Logo  ; Grallert, Harald 21 ; Roden, Michael 12   VIAFID ORCID Logo  ; Võsa, Urmo 17 ; Esko, Tonu 17 ; Hayward, Caroline 22   VIAFID ORCID Logo  ; Johansson, Åsa 7   VIAFID ORCID Logo  ; Gyllensten, Ulf 7   VIAFID ORCID Logo  ; Powell, Nick 8 ; Hansson, Oskar 23   VIAFID ORCID Logo  ; Mattsson-Carlgren, Niklas 24 ; Joshi, Peter K. 4   VIAFID ORCID Logo  ; Danesh, John 25 ; Padyukov, Leonid 26   VIAFID ORCID Logo  ; Klareskog, Lars 26   VIAFID ORCID Logo  ; Landén, Mikael 27   VIAFID ORCID Logo  ; Wilson, James F. 28   VIAFID ORCID Logo  ; Siegbahn, Agneta 29 ; Wallentin, Lars 29 ; Mälarstig, Anders 5   VIAFID ORCID Logo  ; Butterworth, Adam S. 30   VIAFID ORCID Logo  ; Peters, James E. 31   VIAFID ORCID Logo 

1  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
2  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of South Australia, Australian Centre for Precision Health, Unit of Clinical and Health Sciences, Adelaide, Australia (GRID:grid.1026.5) (ISNI:0000 0000 8994 5086); South Australian Health and Medical Research Institute, Adelaide, Australia (GRID:grid.430453.5) (ISNI:0000 0004 0565 2606) 
3  Uppsala University, Uppsala Clinical Research Center, Uppsala, Sweden (GRID:grid.8993.b) (ISNI:0000 0004 1936 9457) 
4  University of Edinburgh, Centre for Global Health Research, Usher Institute, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
5  Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Pfizer Worldwide Research, Development and Medical, Stockholm, Sweden (GRID:grid.4714.6) 
6  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
7  Uppsala University, Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala, Sweden (GRID:grid.8993.b) (ISNI:0000 0004 1936 9457) 
8  Imperial College London, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
9  King’s College London, School of Immunology and Microbial Sciences, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
10  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
11  Nucleus Genomics ltd, New York, USA (GRID:grid.5335.0) 
12  German Diabetes Center, Institute for Clinical Diabetology, Düsseldorf, Germany (GRID:grid.429051.b) (ISNI:0000 0004 0492 602X); Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Department of Endocrinology and Diabetology, Düsseldorf, Germany (GRID:grid.411327.2) (ISNI:0000 0001 2176 9917); German Center for Diabetes Research, Munich-Neuherberg, Germany (GRID:grid.452622.5) 
13  University of Gothenburg, Institute of Neuroscience and Physiology, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582) 
14  Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
15  Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Helmholtz Zentrum München, German Research Center for Environmental Health, Research Unit of Molecular Epidemiology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
16  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Wellcome Genome Campus and University of Cambridge, Health Data Research UK, Hinxton, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
17  University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
18  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); AstraZeneca, Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, Cambridge, UK (GRID:grid.417815.e) (ISNI:0000 0004 5929 4381) 
19  University of Split, Medical School, Split, Croatia (GRID:grid.38603.3e) (ISNI:0000 0004 0644 1675) 
20  German Center for Diabetes Research, Munich-Neuherberg, Germany (GRID:grid.452622.5); Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
21  German Center for Diabetes Research, Munich-Neuherberg, Germany (GRID:grid.452622.5); Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Epidemiology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); Helmholtz Zentrum München, German Research Center for Environmental Health, Research Unit of Molecular Epidemiology, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
22  University of Edinburgh, Western General Hospital, MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.417068.c) (ISNI:0000 0004 0624 9907) 
23  Lund University, Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Skåne University Hospital, Malmö, Sweden (GRID:grid.411843.b) (ISNI:0000 0004 0623 9987) 
24  Lund University, Wallenberg Centre for Molecular Medicine, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Lund University, Clinical Memory Research Unit, Faculty of Medicine, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Skåne University Hospital, Lund University, Department of Neurology, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
25  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Wellcome Genome Campus and University of Cambridge, Health Data Research UK, Hinxton, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Wellcome Sanger Institute, Department of Human Genetics, Hinxton, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
26  Karolinska Institutet and Karolinska University Hospital, Division of Rheumatology, Department of Medicine (Solna), Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Karolinska Institutet, Center for Molecular Medicine, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
27  Karolinska Institutet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); University of Gothenburg, Institute of Neuroscience and Physiology, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582) 
28  University of Edinburgh, Centre for Global Health Research, Usher Institute, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988); University of Edinburgh, Western General Hospital, MRC Human Genetics Unit, Institute of Genetics and Cancer, Edinburgh, UK (GRID:grid.417068.c) (ISNI:0000 0004 0624 9907) 
29  Uppsala University, Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala, Sweden (GRID:grid.8993.b) (ISNI:0000 0004 1936 9457) 
30  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Victor Phillip Dahdaleh Heart and Lung Research Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Wellcome Genome Campus and University of Cambridge, Health Data Research UK, Hinxton, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
31  University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Wellcome Genome Campus and University of Cambridge, Health Data Research UK, Hinxton, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Imperial College London, Department of Immunology and Inflammation, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111) 
Pages
1540-1551
Publication year
2023
Publication date
Sep 2023
Publisher
Nature Publishing Group
ISSN
15292908
e-ISSN
15292916
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41590-023-01588-w
ProQuest document ID
2857176026
Copyright
© The Author(s) 2023. corrected publication 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.