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.