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

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

in 631/1647/1513/2192 / 631/1647/2017 / 631/1647/2017/2065 / 631/250/248 / 692/699/249/1313 / antibody / arthritis / Autoimmune diseases / Basic Medicine / Biomedical and Life Sciences / Biomedicine / CD40 antigen / Colitis, Ulcerative - drug therapy / Colitis, Ulcerative - genetics / Disease / Drug development / eqtl / Etiology / expression / Gene mapping / Genetics / Genome-wide association studies / Genome-Wide Association Study / Genomes / growth / gwas / Health risks / Humans / Immunologi inom det medicinska området / Immunology / Immunology in the Medical Area / Immunosuppressive agents / Infectious Diseases / Inflammation / Inflammation - genetics / Inflammatory bowel diseases / Inflammatory Bowel Diseases - genetics / Lymphotoxin / Medical and Health Sciences / Medical Genetics and Genomics (including Gene Therapy) / Medicin och hälsovetenskap / Medicinsk genetik och genomik (Här ingår: Genterapi) / Medicinska och farmaceutiska grundvetenskaper / Multiple sclerosis / Multiple Sclerosis - genetics / Plasma proteins / Polymorphism, Single Nucleotide / Proteins / Quantitative Trait Loci / receptor / Rheumatoid arthritis / Therapeutic targets / Tumor necrosis factor-β / tweak / Ulcerative colitis

2023

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

2023

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2023

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Journal Article

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

Klareskog, Lars,

Roden, Michael,

Folkersen, Lasse,

Polasek, Ozren,

Johansson, Åsa,

Padyukov, Leonid,

Powell, Nick,

Gyllensten, Ulf,

Eriksson, Niclas,

Hedman, Åsa K.,

Võsa, Urmo,

Hansson, Oskar,

Cozzetto, Domenico,

Wallentin, Lars,

Macdonald-Dunlop, Erin,

Siegbahn, Agneta,

Marten, Jonathan,

Joshi, Peter K.,

Danesh, John,

Needham, Elise J.,

Paul, Dirk S.,

Butterworth, Adam S.,

Landén, Mikael,

Gieger, Christian,

Jonsson, Lina,

Enroth, Stefan,

Grallert, Harald,

Stacey, David,

Digby-Bell, Jonathan,

Mälarstig, Anders,

Mattsson-Carlgren, Niklas,

Thorand, Barbara,

Bergen, Sarah E.,

Esko, Tonu,

Zhao, Jing Hua,

Kalnapenkis, Anette,

Peters, James E.,

Surendran, Praveen,

Wilson, James F.,

Herder, Christian,

Hayward, Caroline

2023

Overview

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.

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