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

doi:10.1038/s41590-023-01588-w

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, Andres Metspalu, Lili Milani, Reedik MägiMari Nelis, Georgi Hudjašov, 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, Estonian Biobank Research Team

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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.

Original language	English
Pages (from-to)	1540-1551
Number of pages	12
Journal	Nature Immunology
Volume	24
Issue number	9
DOIs	https://doi.org/10.1038/s41590-023-01588-w
Publication status	Published - 2023 Sept

Subject classification (UKÄ)

Medical Genetics

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10.1038/s41590-023-01588-w

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Zhao, J. H., Stacey, D., Eriksson, N., Macdonald-Dunlop, E., Hedman, Å. K., Kalnapenkis, A., Enroth, S., Cozzetto, D., Digby-Bell, J., Marten, J., Folkersen, L., Herder, C., Jonsson, L., Bergen, S. E., Gieger, C., Needham, E. J., Surendran, P., Metspalu, A., Milani, L., ... Estonian Biobank Research Team (2023). Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nature Immunology, 24(9), 1540-1551. https://doi.org/10.1038/s41590-023-01588-w

@article{4ae66144b3c943f3b9537c1843a5df0c,

title = "Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets",

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.",

author = "Zhao, {Jing Hua} and David Stacey and Niclas Eriksson and Erin Macdonald-Dunlop and Hedman, {{\AA}sa K.} and Anette Kalnapenkis and Stefan Enroth and Domenico Cozzetto and Jonathan Digby-Bell and Jonathan Marten and Lasse Folkersen and Christian Herder and Lina Jonsson and Bergen, {Sarah E.} and Christian Gieger and Needham, {Elise J.} and Praveen Surendran and Andres Metspalu and Lili Milani and Reedik M{\"a}gi and Mari Nelis and Georgi Hudja{\v s}ov and Paul, {Dirk S.} and Ozren Polasek and Barbara Thorand and Harald Grallert and Michael Roden and Urmo V{\~o}sa and Tonu Esko and Caroline Hayward and {\AA}sa Johansson and Ulf Gyllensten and Nick Powell and Oskar Hansson and Niklas Mattsson-Carlgren and Joshi, {Peter K.} and John Danesh and Leonid Padyukov and Lars Klareskog and Mikael Land{\'e}n and Wilson, {James F.} and Agneta Siegbahn and Lars Wallentin and Anders M{\"a}larstig and Butterworth, {Adam S.} and Peters, {James E.} and {Estonian Biobank Research Team}",

year = "2023",

month = sep,

doi = "10.1038/s41590-023-01588-w",

language = "English",

volume = "24",

pages = "1540--1551",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

number = "9",

}

Zhao, JH, Stacey, D, Eriksson, N, Macdonald-Dunlop, E, Hedman, ÅK, Kalnapenkis, A, Enroth, S, Cozzetto, D, Digby-Bell, J, Marten, J, Folkersen, L, Herder, C, Jonsson, L, Bergen, SE, Gieger, C, Needham, EJ, Surendran, P, Metspalu, A, Milani, L, Mägi, R, Nelis, M, Hudjašov, G, Paul, DS, Polasek, O, Thorand, B, Grallert, H, Roden, M, Võsa, U, Esko, T, Hayward, C, Johansson, Å, Gyllensten, U, Powell, N, Hansson, O , Mattsson-Carlgren, N, Joshi, PK, Danesh, J, Padyukov, L, Klareskog, L, Landén, M, Wilson, JF, Siegbahn, A, Wallentin, L, Mälarstig, A, Butterworth, AS, Peters, JE & Estonian Biobank Research Team 2023, 'Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets', Nature Immunology, vol. 24, no. 9, pp. 1540-1551. https://doi.org/10.1038/s41590-023-01588-w

TY - JOUR

T1 - Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets

AU - Zhao, Jing Hua

AU - Stacey, David

AU - Eriksson, Niclas

AU - Macdonald-Dunlop, Erin

AU - Hedman, Åsa K.

AU - Kalnapenkis, Anette

AU - Enroth, Stefan

AU - Cozzetto, Domenico

AU - Digby-Bell, Jonathan

AU - Marten, Jonathan

AU - Folkersen, Lasse

AU - Herder, Christian

AU - Jonsson, Lina

AU - Bergen, Sarah E.

AU - Gieger, Christian

AU - Needham, Elise J.

AU - Surendran, Praveen

AU - Metspalu, Andres

AU - Milani, Lili

AU - Mägi, Reedik

AU - Nelis, Mari

AU - Hudjašov, Georgi

AU - Paul, Dirk S.

AU - Polasek, Ozren

AU - Thorand, Barbara

AU - Grallert, Harald

AU - Roden, Michael

AU - Võsa, Urmo

AU - Esko, Tonu

AU - Hayward, Caroline

AU - Johansson, Åsa

AU - Gyllensten, Ulf

AU - Powell, Nick

AU - Hansson, Oskar

AU - Mattsson-Carlgren, Niklas

AU - Joshi, Peter K.

AU - Danesh, John

AU - Padyukov, Leonid

AU - Klareskog, Lars

AU - Landén, Mikael

AU - Wilson, James F.

AU - Siegbahn, Agneta

AU - Wallentin, Lars

AU - Mälarstig, Anders

AU - Butterworth, Adam S.

AU - Peters, James E.

AU - Estonian Biobank Research Team

PY - 2023/9

Y1 - 2023/9

N2 - 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.

AB - 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.

U2 - 10.1038/s41590-023-01588-w

DO - 10.1038/s41590-023-01588-w

M3 - Article

C2 - 37563310

AN - SCOPUS:85167517759

SN - 1529-2908

VL - 24

SP - 1540

EP - 1551

JO - Nature Immunology

JF - Nature Immunology

IS - 9

ER -

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

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