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

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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
Nature Immunology ( IF 27.7 ) Pub Date : 2023-08-10 , DOI: 10.1038/s41590-023-01588-w
Jing Hua Zhao _{1,

2} , David Stacey _{1,

2,

3,

4} , Niclas Eriksson ₅ , Erin Macdonald-Dunlop ₆ , Åsa K Hedman _{7,

8} , Anette Kalnapenkis _{1,

9} , Stefan Enroth ₁₀ , Domenico Cozzetto ₁₁ , Jonathan Digby-Bell ₁₂ , Jonathan Marten ₁ , Lasse Folkersen ₁₃ , Christian Herder _{14,

15,

16} , Lina Jonsson ₁₇ , Sarah E Bergen ₇ , Christian Gieger _{18,

19} , Elise J Needham _{1,

2} , Praveen Surendran _{1,

20,

21} , , Dirk S Paul _{1,

2,

20,

22} , Ozren Polasek ₂₃ , Barbara Thorand _{16,

18} , Harald Grallert _{16,

18,

19} , Michael Roden _{14,

15,

16} , Urmo Võsa ₉ , Tonu Esko ₉ , Caroline Hayward ₂₄ , Åsa Johansson ₁₀ , Ulf Gyllensten ₁₀ , Nick Powell ₁₁ , Oskar Hansson _{25,

26} , Niklas Mattsson-Carlgren _{27,

28,

29} , Peter K Joshi ₆ , John Danesh _{1,

2,

20,

21,

30,

31} , Leonid Padyukov _{32,

33} , Lars Klareskog _{32,

33} , Mikael Landén _{7,

17} , James F Wilson _{6,

24} , Agneta Siegbahn ₃₄ , Lars Wallentin ₃₄ , Anders Mälarstig _{7,

8} , Adam S Butterworth _{1,

2,

20,

21,

30} , James E Peters _{1,

21,

35}

Affiliation

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK.
Australian Centre for Precision Health, Unit of Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, Australia.
South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Development and Medical, Pfizer Worldwide Research, Stockholm, Sweden.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Department of Immunology, Genetics, and Pathology, Biomedical Center, SciLifeLab Uppsala, Uppsala University, Uppsala, Sweden.
Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
School of Immunology and Microbial Sciences, King's College London, London, UK.
Nucleus Genomics ltd, New York, NY, USA.
Institute for Clinical Diabetology, German Diabetes Center, Düsseldorf, Germany.
Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
German Center for Diabetes Research, Munich-Neuherberg, Germany.
Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
Health Data Research UK, Wellcome Genome Campus and University of Cambridge, Hinxton, UK.
Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
Medical School, University of Split, Split, Croatia.
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
Skåne University Hospital, Malmö, Sweden.
Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden.
Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.
Department of Human Genetics, Wellcome Sanger Institute, Hinxton, UK.
Division of Rheumatology, Department of Medicine (Solna), Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
Department of Immunology and Inflammation, Imperial College London, London, UK.

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.

中文翻译：

循环炎症蛋白的遗传学确定了免疫介导疾病风险的驱动因素和治疗靶点

循环蛋白在炎症和多种疾病中具有重要功能。为了确定遗传对炎症相关蛋白的影响，我们对 14,824 名参与者使用 Olink Target 平台测量的 91 种血浆蛋白进行了全基因组蛋白数量性状位点 (pQTL) 研究。我们鉴定了 180 个 pQTL（59 个顺式，121 个反式）。 pQTL 数据与 eQTL 和疾病全基因组关联研究的整合提供了对发病机制的深入了解，表明淋巴毒素-α 与多发性硬化症有关。使用孟德尔随机化 (MR) 来评估疾病病因学中的因果关系，我们确定了特定蛋白质在免疫介导疾病中的共同和独特影响，包括 CD40 对类风湿性关节炎与多发性硬化症和炎症性肠病风险的定向不一致影响。 MR 表明 CXCL5 与溃疡性结肠炎 (UC) 的病因有关，我们发现 UC 患者肠道CXCL5转录物表达升高。这些结果确定了现有药物的靶点，并为促进未来药物靶点的优先排序提供了强大的资源。

更新日期：2023-08-11

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