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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 and Marten, Jonathan , et al. (2023) In Nature Immunology 24(9). p.1540-1551
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Immunology
volume
24
issue
9
pages
12 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85167517759
  • pmid:37563310
ISSN
1529-2908
DOI
10.1038/s41590-023-01588-w
language
English
LU publication?
yes
id
4ae66144-b3c9-43f3-b953-7c1843a5df0c
date added to LUP
2023-10-30 13:54:57
date last changed
2024-02-18 21:32:19
@article{4ae66144-b3c9-43f3-b953-7c1843a5df0c,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhao, Jing Hua and Stacey, David and Eriksson, Niclas and Macdonald-Dunlop, Erin and Hedman, Åsa K. and Kalnapenkis, Anette and Enroth, Stefan and Cozzetto, Domenico and Digby-Bell, Jonathan and Marten, Jonathan and Folkersen, Lasse and Herder, Christian and Jonsson, Lina and Bergen, Sarah E. and Gieger, Christian and Needham, Elise J. and Surendran, Praveen and Metspalu, Andres and Milani, Lili and Mägi, Reedik and Nelis, Mari and Hudjašov, Georgi and Paul, Dirk S. and Polasek, Ozren and Thorand, Barbara and Grallert, Harald and Roden, Michael and Võsa, Urmo and Esko, Tonu and Hayward, Caroline and Johansson, Åsa and Gyllensten, Ulf and Powell, Nick and Hansson, Oskar and Mattsson-Carlgren, Niklas and Joshi, Peter K. and Danesh, John and Padyukov, Leonid and Klareskog, Lars and Landén, Mikael and Wilson, James F. and Siegbahn, Agneta and Wallentin, Lars and Mälarstig, Anders and Butterworth, Adam S. and Peters, James E.}},
  issn         = {{1529-2908}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1540--1551}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Immunology}},
  title        = {{Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets}},
  url          = {{http://dx.doi.org/10.1038/s41590-023-01588-w}},
  doi          = {{10.1038/s41590-023-01588-w}},
  volume       = {{24}},
  year         = {{2023}},
}