The effect of inflammatory proteins on COVID-19 is mediated by blood metabolites: A Mendelian randomization study

Several studies have suggested that inflammatory proteins may be associated with Coronavirus disease 2019 (COVID-19). However, the specific causal relationship between the 2 and whether blood metabolites act as mediators remains unclear. Therefore, the purpose of the present study is to investigate the causal relationship between inflammatory proteins and COVID-19 and to identify and quantify the role of blood metabolites as potential mediators. Two-sample Mendelian randomization (MR) and 2-step mediated MR analyses were used to investigate the causal relationships between 91 inflammatory proteins, 486 blood metabolites and COVID-19. A random-effects inverse variance weighted (IVW) approach was used as the primary analytical method, supplemented by weighted medians, MR-Egger and MR multivariate residual sums, and outliers to test MR hypotheses. Our results showed that 2 inflammatory proteins (interleukin-10 and interleukin-18) were positively associated with COVID-19 risk, while 1 inflammatory protein (PD-L1) was negatively associated. Further validation was performed using sensitivity analysis. The results of mediated MR showed that Betaine was a mediator of PD-L1 to COVID-19 with a mediation ratio of 15.92%. Our study suggests a genetic causality between specific inflammatory proteins and COVID-19, highlights the potential mediating role of the blood metabolite betaine, and contributes to a deeper understanding of the mechanism of action of severe COVID-19.