Plasma apolipoprotein A-I is a causal protective factor in sepsis

Area of Science:

• Genetics and Genomics
• Cardiovascular Biology
• Infectious Diseases

Background:

• Apolipoprotein AI (ApoAI), a key component of high-density lipoprotein (HDL), plays a role in binding pathogen lipids and modulating inflammation.
• Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, often involving inflammation and organ dysfunction.

Purpose of the Study:

• To investigate the causal role of Apolipoprotein AI (ApoAI) in sepsis incidence and mortality.
• To explore the potential mechanism by which ApoAI exerts its protective effects in sepsis, specifically its impact on circulating lipopolysaccharide (LPS) levels.

Main Methods:

• Retrospective analysis of 442,601 European patients from the UK Biobank (UKB) cohort, focusing on 11,643 sepsis patients.
• Mendelian randomization (MR) analysis using an ApoAI genetic score as an instrumental variable to assess causality.
• Sensitivity analyses and validation in transancestry sepsis cohorts (VASST and Chiba) to confirm findings and assess independence from other lipid parameters.

Main Results:

• Lower median baseline ApoAI levels were observed in individuals who developed sepsis compared to those who did not (P < 0.0001).
• MR analysis demonstrated that ApoAI is causally protective against sepsis incidence (OR=0.87) and 28-day mortality (OR=0.73) in the UKB cohort.
• The protective effect of ApoAI on sepsis mortality was validated in European (VASST) and East Asian (Chiba) cohorts, with overlapping confidence intervals.
• ApoAI was found to causally reduce circulating LPS levels (logOR=-0.23), suggesting a potential mechanism for its protective role.

Conclusions:

• Plasma ApoAI levels confer significant causal protection against sepsis pathobiology.
• The protective effect of ApoAI in sepsis may be mediated, at least in part, by its ability to reduce circulating LPS levels.
• These findings highlight ApoAI as a potential therapeutic target for sepsis management.