Identification of potential therapeutic drug targets for sepsis by combining the human plasma proteome and genome: a Mendelian randomization study.

BACKGROUND

Currently, sepsis has an extremely high mortality rate and no specific treatment. Mendelian Randomization (MR) can utilize genetic variants as instrumental variables (IVs) to infer causal relationships between protein biomarkers and sepsis. We conducted a proteome-wide MR study to identify biological markers and therapeutic targets associated with sepsis.

METHODS

The protein quantitative trait locus (pQTL) were analyzed using two data sources: 734 proteins from Zheng ; and 4,907 proteins from the deCODE database. The causal relationship between the candidate proteins and sepsis was then verified by a two-sample MR analysis, colocalization analysis, and summary data-based Mendelian randomization (SMR) analysis. A protein-protein interaction (PPI) analysis, transcriptome difference analysis, single-cell expression analysis, and druggability assessment were also performed to detect specific cell types and rank therapeutic targets.

RESULTS

Elevated levels of CD33 [odds ratio (OR) 1.04, 95% confidence interval (CI): 1.02-1.05, P=0.006] and LY9 (OR 1.10, 95% CI: 1.05-1.15, P=0.01) were associated with an increased risk of sepsis, which were considered convincing evidence. CD33 is predominantly seen in acute myeloid leukemia (AML) and Alzheimer's disease (AD), and relevant related drugs are currently in development. While LY9 is predominantly seen in multiple sclerosis, but information on its related drugs is lacking. Both proteins may be potential targets for sepsis.

CONCLUSIONS

This study identified several protein biomarkers associated with the risk of sepsis, provided novel insights into the etiology of sepsis, and identified promising targets (CD33 and LY9) for the development of therapeutic drugs for sepsis.