Mapping pQTLs of circulating inflammatory proteins identifies drivers of immune-related disease risk and novel therapeutic targets
medrxiv(2023)
Abstract
Circulating proteins play key roles 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 15,150 participants. We identified 180 pQTLs, of which 50 were novel. Integration of pQTL data with eQTL and disease GWAS provided insights into pathogenesis, implicating lymphotoxin-alpha (LTA) in multiple sclerosis. Using Mendelian randomisation (MR), we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant causal roles for CD40 in rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Our results highlight novel potential therapeutic avenues, including CXCL5 in ulcerative colitis (UC), a finding supported by elevated gut CXCL5 expression in UC patients. Our data provide a powerful resource to facilitate future drug target prioritization.
### Competing Interest Statement
John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING), member, London (since 2013); the MRC High Throughput Science Omics, panel member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the AstraZeneca Genomics Advisory Board (2018). Adam S. Butterworth has received grants unrelated to this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis and Sanofi. James E. Peters has received hospitality and travel expenses to speak at Olink-sponsored academic meetings (none within the past 5 years). During the drafting of the manuscript, Dirk S. Paul became a full-time employee of AstraZeneca, and Praveen Surendran became a full-time employee of GlaxoSmithKline. Mikael Landen declares that he has received lecture honoraria from Lundbeck pharmaceutical.
### Funding Statement
James Peters was supported by a Medical Research Foundation grant (MRF-042-0001-RG-PETE-C0839). E.J.N was supported by the Schmidt Science Fellows, in partnership with the Rhodes Trust. Praveen Surendran was supported by a Rutherford Fund Fellowship from the Medical Research Council (grant no. MR/S003746/1). John Danesh holds a British Heart Foundation Professorship and a NIHR Senior Investigator Award*. Caroline Hayward is supported by an MRC University Unit Programme Grant QTL in Health and Disease (U.MC\_UU\_00007/10). *The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Funding of the GWAS and proteomics studies of STABILITY and ARISTOTLE: These studies were supported by GlaxoSmithKline, BristolMyersSquibb, and the Swedish Foundation for Strategic Research (grant number RB13-0197). The Orkney Complex Disease Study (ORCADES) was supported by the Chief Scientist Office of the Scottish Government (CZB/4/276, CZB/4/710), a Royal Society URF to J.F.W., the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease, 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. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of 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 National Institute for Health and Care Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) [*]. The academic coordinating centre for INTERVAL was supported by core funding from the: NIHR Blood and Transplant Research Unit (BTRU) in Donor Health and Genomics (NIHR BTRU-2014-10024), NIHR BTRU in Donor Health and Behaviour (NIHR203337), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and NIHR Cambridge BRC (BRC-1215-20014; NIHR203312) [*]. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference [**]. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, 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. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. *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. **Di Angelantonio E, Thompson SG, Kaptoge SK, Moore C, Walker M, Armitage J, Ouwehand WH, Roberts DJ, Danesh J, INTERVAL Trial Group. Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45,000 donors. Lancet. 2017 Nov 25;390(10110):2360-2371. Estonian Biobank work was supported by the European Regional Development Fund and the programme Mobilitas Pluss (MOBTP108), No. 2014-2020.4.01.15-0012 GENTRANSMED and 2014-2020.4.01.16-0125 This study was also funded by the EU H2020 grant 692145, by the Estonian Research Council Grant PUT1660 and by the Estonian Research Council grant PUT (PRG1291). Data analyzes with Estonian datasets were carried out in part in the High-Performance Computing Center of University of Tartu. The SWEBIC biobank was supported by the Stanley Medical Research Institute. The proteomic analyses in SWEBIC was funded by the Swedish foundation for Strategic Research (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 agreement no. 2018-05973. The CROATIA-Vis study was funded by grants from the Medical Research Council (UK), from the Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302; 216-1080315-0302) and the Croatian Science Foundation (8875). The KORA study was initiated and financed by the Helmholtz Zentrum Munchen - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universitat, 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. This study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD).
### Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The Estonian Committee on Bioethics and Human Research (1.1-12/624) and the Research Ethics Committee of the University of Tartu (application number 262/T-3, October 2016) gave ethical approval for this work. The Cambridge (East) Research Ethics Committee gave ethical approval for the INTERVAL study. The Research Ethics Committees in Orkney, Aberdeen (North of Scotland REC), and South East Scotland REC, NHS Lothian (reference: 12/SS/0151) have ethical approval for the ORCADES study. Ethical approval for SWEBIC was granted by the Regional Ethical Review Board in Stockholm, Sweden (2008/2009-31/2). The Research Ethics Committees in Croatia (Institutional Ethics Committee of the University of Split School of Medicine [protocol code 2181-198-03-04/10-11-0008] gave ethical approval for VIS.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
All data produced in the present study are available upon reasonable request to the authors. Full per-protein summary statistics will be made available on publication of the peer-reviewed journal article.
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