Low apolipoprotein A-II levels causally contribute to increased mortality in septic shock.

Summary

Across Japanese and Caucasian cohorts with septic shock, lower apolipoprotein A-II levels and an ApoA2 variant (rs6413453 GG) were associated with higher mortality and more organ dysfunction. Mendelian randomization supported a causal effect of decreased ApoA-II on mortality. These findings implicate host lipid biology as a modifiable determinant of sepsis outcomes.

Key Findings

• In the Japan cohort (n=687), lower apolipoprotein A-II levels were associated with higher in-hospital mortality (adjusted OR 1.05 per 1 mg/dL decrease; 95% CI 1.02–1.09; P<0.001).
• ApoA2 rs6413453 GG genotype conferred increased 28-day mortality (aHR 1.79; 95% CI 1.06–3.04) and fewer organ failure–free days; replicated in the VASST Caucasian cohort (aHR 1.65; 95% CI 1.02–2.68).
• Mendelian randomization using 9 SNPs indicated a causal effect: each 1 mg/dL genetically decreased ApoA-II increased mortality risk (OR 1.05; 95% CI 1.01–1.03; P=0.0022).

Clinical Implications

ApoA-II could inform early risk stratification in septic shock and motivate trials of HDL/apolipoprotein-targeted interventions (e.g., HDL mimetics, apolipoprotein infusions, or metabolic modulators). Routine measurement is not yet indicated but may be considered in research or precision-medicine programs.

Limitations

• Observational design for biomarker-outcome associations; residual confounding cannot be fully excluded.
• Findings focus on septic shock ICU populations; generalizability to broader sepsis phenotypes remains to be tested.

Future Directions

Prospective trials of ApoA-II/HDL-raising strategies (e.g., HDL infusions, apoA-I/II mimetics), validation of clinical risk scores incorporating ApoA-II, and mechanistic studies dissecting lipoprotein–immune interactions in sepsis.