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

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Zhao, Jing Hua 
Stacey, David 
Macdonald-Dunlop, Erin  ORCID logo
Hedman, Åsa K 

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.

Humans, Genome-Wide Association Study, Inflammatory Bowel Diseases, Quantitative Trait Loci, Colitis, Ulcerative, Inflammation, Multiple Sclerosis, Polymorphism, Single Nucleotide
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Nat Immunol
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Springer Science and Business Media LLC
National Institute for Health and Care Research (IS-BRC-1215-20014)
Department of Health (via National Institute for Health Research (NIHR)) (NIHR BTRU-2014-10024)
Department of Health (via National Institute for Health Research (NIHR)) (NIHR203337)
Medical Research Council (MR/L003120/1)
British Heart Foundation (SP/09/002/27676)
British Heart Foundation (RG/18/13/33946)
British Heart Foundation (None)
Medical Research Council (MR/S003746/1)