Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Jing Hua Zhao; David Stacey; Niclas Eriksson; Erin Macdonald-Dunlop; Åsa K Hedman; Anette Kalnapenkis; Stefan Enroth; Domenico Cozzetto; Jonathan Digby-Bell; Jonathan Marten; Lasse Folkersen; Christian Herder; Lina Jonsson; Sarah E Bergen; Christian Gieger; Elise J Needham; Praveen Surendran; Estonian Biobank Research Team; Dirk S Paul; Ozren Polasek; Barbara Thorand; Harald Grallert; Michael Roden; Urmo Võsa; Tonu Esko; Caroline Hayward; Åsa Johansson; Ulf Gyllensten; Nick Powell; Oskar Hansson; Niklas Mattsson-Carlgren; Peter K Joshi; John Danesh; Leonid Padyukov; Lars Klareskog; Mikael Landén; James F Wilson; Agneta Siegbahn; Lars Wallentin; Anders Mälarstig; Adam S Butterworth; James E Peters

doi:10.1038/s41590-023-01588-w

Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

Nat Immunol. 2023 Sep;24(9):1540-1551. doi: 10.1038/s41590-023-01588-w. Epub 2023 Aug 10.

Authors

Jing Hua Zhao^#^{1

2}, David Stacey^#^{1

2

3

4}, Niclas Eriksson⁵, Erin Macdonald-Dunlop⁶, Åsa K Hedman^{7

8}, Anette Kalnapenkis^{1

9}, Stefan Enroth¹⁰, Domenico Cozzetto¹¹, Jonathan Digby-Bell¹², Jonathan Marten¹, Lasse Folkersen¹³, Christian Herder^{14

15

16}, Lina Jonsson¹⁷, Sarah E Bergen⁷, Christian Gieger^{18

19}, Elise J Needham^{1

2}, Praveen Surendran^{1

20

21}; Estonian Biobank Research Team; Dirk S Paul^{1

2

20

22}, Ozren Polasek²³, Barbara Thorand^{16

18}, Harald Grallert^{16

18

19}, Michael Roden^{14

15

16}, Urmo Võsa⁹, Tonu Esko⁹, Caroline Hayward²⁴, Åsa Johansson¹⁰, Ulf Gyllensten¹⁰, Nick Powell¹¹, Oskar Hansson^{25

26}, Niklas Mattsson-Carlgren^{27

28

29}, Peter K Joshi⁶, John Danesh^{1

2

20

21

30

31}, Leonid Padyukov^{32

33}, Lars Klareskog^{32

33}, Mikael Landén^{7

17}, James F Wilson^{6

24}, Agneta Siegbahn³⁴, Lars Wallentin³⁴, Anders Mälarstig^{7

8}, Adam S Butterworth^{35

36

37

38

39}, James E Peters^{40

41

42}

Collaborators

Estonian Biobank Research Team:
Andres Metspalu, Lili Milani, Reedik Mägi, Mari Nelis, Georgi Hudjašov

Affiliations

¹ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
³ Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
⁴ South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
⁵ Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
⁶ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
⁷ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁸ Development and Medical, Pfizer Worldwide Research, Stockholm, Sweden.
⁹ Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
¹⁰ Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala, Sweden.
¹¹ Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
¹² School of Immunology and Microbial Sciences, King's College London, London, UK.
¹³ Nucleus Genomics ltd, New York, NY, USA.
¹⁴ Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
¹⁵ Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁶ German Center for Diabetes Research, Munich-Neuherberg, Germany.
¹⁷ Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
¹⁸ Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
¹⁹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²⁰ British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
²¹ Health Data Research UK, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.
²² Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
²³ Medical School, University of Split, Split, Croatia.
²⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
²⁵ Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
²⁶ Skåne University Hospital, Malmö, Sweden.
²⁷ Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
²⁸ Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
²⁹ Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
³⁰ NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
³¹ Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
³² Division of Rheumatology, Department of Medicine (Solna), Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
³³ Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
³⁴ Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
³⁵ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [email protected].
³⁶ Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK. [email protected].
³⁷ British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK. [email protected].
³⁸ Health Data Research UK, Wellcome Genome Campus and University of Cambridge, Hinxton, UK. [email protected].
³⁹ NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK. [email protected].
⁴⁰ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [email protected].
⁴¹ Health Data Research UK, Wellcome Genome Campus and University of Cambridge, Hinxton, UK. [email protected].
⁴² Department of Immunology and Inflammation, Imperial College London, London, UK. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colitis, Ulcerative* / drug therapy
Colitis, Ulcerative* / genetics
Genome-Wide Association Study
Humans
Inflammation / genetics
Inflammatory Bowel Diseases* / genetics
Multiple Sclerosis* / genetics
Polymorphism, Single Nucleotide
Quantitative Trait Loci

Abstract

Publication types

MeSH terms

Grants and funding