@article{da67dd4b1fb44ef69e190dacad8d332b,
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 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}",
note = "Funding Information: This work was performed under the auspices of the SCALLOP Consortium. We thank the following: study participants from the contributing cohorts; the International Multiple Sclerosis Genetics Consortium, which provided multiple sclerosis GWAS summary statistics used in our analyses; A. Siopi and D. McLeod for support with SCALLOP Consortium administration; the authors of the GCTA software for advice; B. Prins for help with the INTERVAL study genotype data quality control; and A. Richard for comments on the manuscript. J.E.P was supported by a grant and fellowship from the Medical Research Foundation (grant nos. MRF-042-0001-RG-PETE-C0839 and MRF-057-0003-RG-PETE-C0799). E.J.N. was supported by the Schmidt Science Fellows, in partnership with the Rhodes Trust. P.S. was supported by a Rutherford Fund Fellowship from the UK Medical Research Council (MRC; grant no. MR/S003746/1). J.D. holds a British Heart Foundation Professorship and a National Institute for Health and Care Research (NIHR) Senior Investigator Award*. C. Ha is supported by an MRC University Unit Programme Grant {\textquoteleft}QTL in Health and Disease{\textquoteright} (grant no. U.MC_UU_00007/10). Funding of the GWASs and proteomics studies of STABILITY and ARISTOTLE were supported by GlaxoSmithKline, BristolMyersSquibb and the Swedish Foundation for Strategic Research (grant no. RB13-0197). The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government (grant nos. CZB/4/276 and CZB/4/710), a Royal Society University Research Fellowship to J.F.W., the MRC Human Genetics Unit quinquennial program {\textquoteleft}QTL in Health and Disease{\textquoteright}, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. We acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any author-accepted manuscript version arising from this submission. Participants in the INTERVAL trial were recruited with the active collaboration of National Health Service (NHS) Blood and Transplant England (www.nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping were co-funded by the NIHR, the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR Cambridge Biomedical Research Centre (grant no. BRC-1215-20014). The academic coordinating center for INTERVAL was supported by core funding from: the NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics (grant no. NIHR BTRU-2014-10024), NIHR BTRU in Donor Health and Behaviour (grant no. NIHR203337), MRC (grant no. MR/L003120/1), British Heart Foundation (grant nos. SP/09/002, RG/13/13/30194 and RG/18/13/33946) and NIHR Cambridge BRC (grant nos. Funding Information: This work was performed under the auspices of the SCALLOP Consortium. We thank the following: study participants from the contributing cohorts; the International Multiple Sclerosis Genetics Consortium, which provided multiple sclerosis GWAS summary statistics used in our analyses; A. Siopi and D. McLeod for support with SCALLOP Consortium administration; the authors of the GCTA software for advice; B. Prins for help with the INTERVAL study genotype data quality control; and A. Richard for comments on the manuscript. J.E.P was supported by a grant and fellowship from the Medical Research Foundation (grant nos. MRF-042-0001-RG-PETE-C0839 and MRF-057-0003-RG-PETE-C0799). E.J.N. was supported by the Schmidt Science Fellows, in partnership with the Rhodes Trust. P.S. was supported by a Rutherford Fund Fellowship from the UK Medical Research Council (MRC; grant no. MR/S003746/1). J.D. holds a British Heart Foundation Professorship and a National Institute for Health and Care Research (NIHR) Senior Investigator Award*. C. Ha is supported by an MRC University Unit Programme Grant {\textquoteleft}QTL in Health and Disease{\textquoteright} (grant no. U.MC_UU_00007/10). Funding of the GWASs and proteomics studies of STABILITY and ARISTOTLE were supported by GlaxoSmithKline, BristolMyersSquibb and the Swedish Foundation for Strategic Research (grant no. RB13-0197). The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government (grant nos. CZB/4/276 and CZB/4/710), a Royal Society University Research Fellowship to J.F.W., the MRC Human Genetics Unit quinquennial program {\textquoteleft}QTL in Health and Disease{\textquoteright}, Arthritis Research UK and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. We acknowledge the invaluable contributions of the research nurses in Orkney, the administrative team in Edinburgh and the people of Orkney. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any author-accepted manuscript version arising from this submission. Participants in the INTERVAL trial were recruited with the active collaboration of National Health Service (NHS) Blood and Transplant England ( www.nhsbt.nhs.uk ), which has supported field work and other elements of the trial. DNA extraction and genotyping were co-funded by the NIHR, the NIHR BioResource ( http://bioresource.nihr.ac.uk ) and the NIHR Cambridge Biomedical Research Centre (grant no. BRC-1215-20014). The academic coordinating center for INTERVAL was supported by core funding from: the NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics (grant no. NIHR BTRU-2014-10024), NIHR BTRU in Donor Health and Behaviour (grant no. NIHR203337), MRC (grant no. MR/L003120/1), British Heart Foundation (grant nos. SP/09/002, RG/13/13/30194 and RG/18/13/33946) and NIHR Cambridge BRC (grant nos. BRC-1215-20014 and NIHR203312)* and has received funding from a European Commission Innovative Medicines Initiative (BigData@Heart). The academic coordinating center thank blood donor center staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the MRC, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome. Estonian Biobank work was supported by the European Regional Development Fund and the program Mobilitas Pluss (MOBTP108, grant nos. 2014-2020.4.01.15-0012 GENTRANSMED and 2014-2020.4.01.16-0125). The present study was also funded by the EU H2020 (grant no. 692145), the Estonian Research Council (grant nos. PUT1660 and PUT PRG1291). Data analyses with Estonian datasets were carried out in part in the High-Performance Computing Center of the University of Tartu. The SWEBIC biobank was supported by the Stanley Medical Research Institute. The proteomic analyses in SWEBIC were funded by the Swedish foundation for Strategic Research (grant no. KF10-0039). For RECOMBINE and SWEBIC, the data handling and analysis were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC), partially funded by the Swedish Research Council through grant no. 2018-05973. The CROATIA-Vis study was funded by grants from the UK MRC, the Republic of Croatia Ministry of Science, Education and Sports (grant nos. 108-1080315-0302 and 216-1080315-0302) and the Croatian Science Foundation (grant no. 8875). We thank the staff of several institutions in Croatia who supported the field work, including Zagreb Medical Schools, the Institute for Anthropological Research in Zagreb, the recruitment team from the Croatian Centre for Global Health, University of Split and all the study participants. The KORA study was initiated and financed by the Helmholtz Zentrum M{\"u}nchen—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences, Ludwig-Maximilians-Universit{\"a}t, as part of LMUinnovativ. The measurement of inflammatory biomarkers was funded by a grant from the German Center for Diabetes Research (DZD; to C. Herder and B. Thorand). This work was also supported by the Ministry of Culture and Science of the State of North Rhine-Westphalia and the German Federal Ministry of Health. The present study was supported in part by a grant from the German Federal Ministry of Education and Research to the DZD. N.P. is supported by a Wellcome Trust Discovery award (no. 225875/Z/22/Z). D.C. is supported by the NIHR Imperial Biomedical Research Centre (BRC)*. Infrastructure support for this research was provided by the NIHR Imperial BRC. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. We acknowledge the Danish node of the TRYGGVE server and the University of Cambridge{\textquoteright}s High Performance Computing cluster, on which computations were performed. *The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, NHSBT or the Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = sep,
day = "1",
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",
}