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

被引：257

作者：

Zhao, Jing Hua ^{[1
,2
]}

Stacey, David ^{[1
,2
,3
,4
]}

Eriksson, Niclas ^{[5
]}

Macdonald-Dunlop, Erin ^{[6
]}

Hedman, Asa K. ^{[7
,8
]}

Kalnapenkis, Anette ^{[1
,9
]}

Enroth, Stefan ^{[10
]}

Cozzetto, Domenico ^{[11
]}

Digby-Bell, Jonathan ^{[12
]}

Marten, Jonathan ^{[1
]}

Folkersen, Lasse ^{[13
]}

Herder, Christian ^{[14
,15
,17
]}

Jonsson, Lina ^{[18
]}

Bergen, Sarah E. ^{[7
]}

Gieger, Christian ^{[16
,19
,20
]}

Needham, Elise J. ^{[2
]}

Surendran, Praveen ^{[1
,21
,22
,23
]}

Metspalu, Andres ^{[9
]}

Milani, Lili ^{[9
]}

Magi, Reedik ^{[9
]}

Nelis, Mari ^{[9
]}

Hudjasov, Georgi ^{[9
]}

Paul, Dirk S. ^{[2
,21
,24
]}

Polasek, Ozren ^{[25
]}

Thorand, Barbara ^{[17
,19
]}

Grallert, Harald ^{[17
,19
,20
]}

Roden, Michael ^{[14
,15
,16
,17
]}

Vosa, Urmo ^{[9
]}

Esko, Tonu ^{[9
]}

Hayward, Caroline ^{[26
]}

Johansson, Asa ^{[10
]}

Gyllensten, Ulf ^{[10
]}

Powell, Nick ^{[11
]}

Hansson, Oskar ^{[27
,28
]}

Mattsson-Carlgren, Niklas ^{[29
,30
,31
]}

Joshi, Peter K. ^{[6
]}

Danesh, John ^{[1
,2
,21
,22
,23
,32
,33
]}

Padyukov, Leonid ^{[34
,35
,36
]}

Klareskog, Lars ^{[34
,35
,36
]}

Landen, Mikael ^{[7
,18
]}

Wilson, James F. ^{[6
,26
]}

Siegbahn, Agneta ^{[37
,38
]}

Wallentin, Lars ^{[37
,38
]}

Malarstig, Anders ^{[7
,8
]}

Butterworth, Adam S. ^{[1
,2
,21
,32
]}

Peters, James E. ^{[1
,22
,23
,39
]}

机构：

[1] Univ Cambridge, Dept Publ Hlth & Primary Care, British Heart Fdn Cardiovasc Epidemiol Unit, Cambridge, England

[2] Univ Cambridge, Victor Phillip Dahdaleh Heart & Lung Res Inst, Cambridge, England

[3] Univ South Australia, Unit Clin & Hlth Sci, Australian Ctr Precis Hlth, Adelaide, SA, Australia

[4] South Australian Hlth & Med Res Inst, Adelaide, SA, Australia

[5] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden

[6] Univ Edinburgh, Usher Inst, Ctr Global Hlth Res, Edinburgh, Midlothian, Scotland

[7] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[8] Pfizer Worldwide Res, Dev & Med, Stockholm, Sweden

[9] Univ Tartu, Inst Genom, Estonian Genome Ctr, Tartu, Estonia

[10] Uppsala Univ, Biomed Ctr, Dept Immunol Genet & Pathol, Uppsala, Sweden

[11] Imperial Coll London, Dept Metab Digest & Reprod, Fac Med, London, England

[12] Kings Coll London, Sch Immunol & Microbial Sci, London, England

[13] Nucleus Genom Itd, New York, NY USA

[14] German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany

[15] Heinrich Heine Univ Dusseldorf, Med Fac, Dept Endocrinol & Diabetol, Dusseldorf, Germany

[16] Heinrich Heine Univ Dusseldorf, Univ Hosp Dusseldorf, Dusseldorf, Germany

[17] German Ctr Diabet Res, Munich, Germany

[18] Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden

[19] German Res Ctr Environm Hlth, Inst Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[20] German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany

[21] Univ Cambridge, Sch Clin Med, Addenbrookes Hosp, British Heart Fdn Ctr Res Excellence, Cambridge, England

[22] Health Data Res UK, Wellcome Genome Campus, Hinxton, England

[23] Univ Cambridge, Hinxton, England

[24] AstraZeneca, Ctr Genom Res, Discovery Sci, BioPharmaceut R&D, Cambridge, England

[25] Univ Split, Med Sch, Split, Croatia

[26] Univ Edinburgh, Inst Genet & Canc, Western Gen Hosp, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

[27] Lund Univ, Dept Clin Sci Malmo, Clin Memory Res Unit, Lund, Sweden

[28] Skane Univ Hosp, Malmo, Sweden

[29] Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden

[30] Lund Univ, Clin Memory Res Unit, Fac Med, Lund, Sweden

[31] Lund Univ, Skane Univ Hosp, Dept Neurol, Lund, Sweden

[32] Univ Cambridge, NIHR Blood & Transplant Res Unit Donor Hlth & Beh, Cambridge, England

[33] Wellcome Sanger Inst, Dept Human Genet, Hinxton, England

[34] Karolinska Inst, Dept Med Solna, Div Rheumatol, Stockholm, Sweden

[35] Karolinska Univ Hosp, Stockholm, Sweden

[36] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden

[37] Uppsala Univ, Dept Med Sci, Uppsala, Sweden

[38] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden

[39] Imperial Coll London, Dept Immunol & Inflammat, London, England

来源：

NATURE IMMUNOLOGY | 2023年 / 24卷 / 09期

基金：

英国医学研究理事会; 欧盟地平线“2020”; 英国经济与社会研究理事会; 英国惠康基金; 英国工程与自然科学研究理事会;

关键词：

GROWTH; EXPRESSION; ARTHRITIS; ANTIBODY; RECEPTOR; TWEAK; GWAS; EQTL;

D O I：

10.1038/s41590-023-01588-w

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-alpha 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.

引用

页码：1540 / +

页数：28

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