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, Dirk S Paul, Ozren Polasek, Barbara ThorandHarald 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1540-1551
Number of pages31
JournalNature Immunology
Issue number9
Early online date10 Aug 2023
Publication statusPublished - 1 Sept 2023


Dive into the research topics of 'Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets'. Together they form a unique fingerprint.

Cite this