Plasma proteomic associates of infection mortality in UK Biobank

Background: Infectious diseases are a major cause of mortality in spite of existing public health, anti-microbial and vaccine interventions. We aimed to define plasma proteomic associates of infection mortality and then apply Mendelian randomisation (MR) to yield biomarkers that may be causally associated. Methods: We used UK Biobank plasma proteomic data to associate 2,923 plasma proteins with infection mortality before 31st December 2019 (240 events in 52,520 participants). Since many plasma proteins also predict non-infection mortality, we focussed on those associated with >1.5-fold risk of infection mortality in an analysis excluding survivors. Protein quantitative trait scores (pQTS) were then used to identify whether genetically predicted protein levels also associated with infection mortality. To conduct Two Sample MR, we performed a genome-wide association study (GWAS) of infection mortality using UK Biobank participants without plasma proteomic data (n=363,953 including 984 infection deaths). Findings: After adjusting for clinical risk factors, 1,142 plasma proteins were associated with risk of infection mortality (false discovery rate <0.05). 259 proteins were associated with >1.5-fold increased risk of infection versus non-infection mortality. Of these, we identified genetically predicted increasing MERTK concentration was associated with increased risk of infection mortality. GWAS for infection mortality revealed no SNPs achieving genome-wide statistical significance (p<5x10-8). However, MR supported a causal association between increasing plasma MERTK protein and infection mortality (odds ratio 1.46 per unit; 95% CI 1.15-1.85; p=0.002). Interpretation: Plasma proteomics demonstrates many proteins are associated with infection mortality. MERTK warrants exploration as a potential therapeutic target. ### Competing Interest Statement RMC has received speakers fees from Janssen Oncology. AWM has received speakers fees from Vifor consultancy fees from Vifor and AstraZenca on behalf of the University of Leeds and investigator-initiated project funding from Roche Products Limited in the last 3 years. ### Funding Statement This work was supported by the British Heart Foundation (RG/F/22/110076). ### 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: All participants gave their written consent and UK Biobank received ethical approval from the NHS Research Ethics Service (11/NW/0382). Our analysis was conducted under application number 98520. 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 The UK Biobank resource is open to all bona fide researchers. The GWAS summary statistics generated will be deposited to the GWAS Catalog (https://www.ebi.ac.uk/gwas/) once the final per reviewed manuscript is published.