Evaluating the Causal Effects of Circulating Proteome on the Risk of Sepsis and Related Outcomes

Abstract

The current investigation deployed Mendelian randomization (MR) to elucidate the causal relationship between circulating proteins and sepsis. A rigorous two-sample MR analysis evaluated the effect of plasma proteins on the sepsis susceptibility. To affirm the integrity of MR findings, a suite of supplementary analyses, including Bayesian colocalization, Steiger filtering, the assessment of protein-altering polymorphisms, and the correlation between expression quantitative trait loci and protein quantitative trait loci (pQTLs), was employed. The study further integrated the examination of protein-protein interactions and pathway enrichment, along with the identification of pharmacologically actionable targets, to advance our comprehension and outline potential sepsis therapies. Subsequent analyses leveraging cis-pQTLs within MR studies unveiled noteworthy relationships: 94 specific proteins exhibited significant links with sepsis-related 28 day mortality, while 96 distinct proteins correlated with survival outcomes in sepsis. Furthermore, incorporating both cis- and trans-pQTLs in MR investigations revealed more comprehensive findings, associating 201 unique proteins with sepsis-related 28 day mortality and 199 distinct proteins with survival outcomes in sepsis. Markedly, colocalization analyses confirmed that eight of these proteins exhibited prominent evidence for colocalization, emphasizing their potential criticality in sepsis pathophysiology. Further in silico analyses were conducted to delineate putative regulatory networks and to highlight prospective drug targets among these proteins. Employing the MR methodology has shed light on plasma proteins implicated in the etiopathogenesis of sepsis. This novel approach unveiled numerous biomarkers and targets, providing a scientific rationale for the development of new therapeutic strategies and prophylactic measures against sepsis.

Figure 1

Flowchart of the MR-based analytical framework for evaluating the effect of plasma proteome on sepsis.

Figure 2

Volcano plot for the cis-only MR analyses, with circles representing the results for proteins on sepsis. (A) Volcano plot of cis-pQTL on sepsis (28 day mortality); (B) volcano plot of cis-pQTL on sepsis (death vs survived); (C) volcano plot of cis + trans-pQTL on sepsis (28 day mortality); and (D) volcano plot of cis + trans-pQTL-pQTL on sepsis (death vs survived).