Tianlong Zhang ¹ Yin Shi ² Jiayue Li ³ Peiyao Huang ⁴ Kun Chen ⁵ Jiali Yao ^5*

• ¹ Department of Critical Care Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
• ² Department of Internal Medicine,, Yiwu Maternity and Children Health Care Hospital, Jinhua, China
• ³ Department of Anesthesiology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
• ⁴ Department of Gastroenterology, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
• ⁵ Department of Critical Care Medicine, Jinhua Hospital Affiliated to Zhejiang University, Jinhua, Zhejiang Province, China

Background: Sepsis is an inflammatory disease that leads to severe mortality, highlighting the urgent need to identify new therapeutic strategies for sepsis. Proteomic research serves as a primary source for drug target identification. We employed proteome-wide Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to identify potential targets for sepsis and sepsis-related death.Genetic data for plasma proteomics were obtained from 35,559 Icelandic individuals and an initial MR analysis was conducted using 13,531 sepsis cases from the FinnGen R10 cohort to identify associations between plasma proteins and sepsis. Subsequently, significant proteins underwent genetic correlation analysis, followed by replication in 54,306 participants from the UK Biobank Pharma Proteomics Project and validation in 11,643 sepsis cases from the UK Biobank. The identified proteins were then subjected to colocalization analysis, enrichment analysis, and protein-protein interaction network analysis. Additionally, we also investigated a MR analysis using plasma proteins on 1,896 sepsis cases with 28-day mortality from the UK Biobank.After FDR correction, MR analysis results showed a significant causal relationship between 113 plasma proteins and sepsis. Genetic correlation analysis revealed that only 8 proteins had genetic correlations with sepsis. In the UKB-PPP replication analysis, only 4 proteins were found to be closely associated with sepsis, while validation in the UK Biobank sepsis cases found overlaps for 21 proteins. In total, 30 proteins were identified in the aforementioned analyses, and colocalization analysis revealed that only 2 of these proteins were closely associated with sepsis. Additionally, in the 28-day mortality MR analysis of sepsis, we also found that only 2 proteins were significant.The identified plasma proteins and their associated metabolic pathways have enhanced our understanding of the complex relationship between proteins and sepsis. This provides new avenues for the development of drug targets and paves the way for further research in this field.