Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1
Authors' conclusion
We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation.
Study context
- Population
- Children with septic shock; juvenile Pcsk9 null and wildtype mice with cecal slurry sepsis
- Participants
- 474 children
- Comparison
- PCSK9 loss-of-function (LOF) genotype vs no LOF
- Primary endpoint
- Influence of PCSK9 LOF genotype on day 1 serum endothelial dysfunction markers
- Follow-up
- Day 1
Methodological detailsmultivariable linear regression, causal mediation analysis, murine sepsis model
- Multivariable linear regression
- Causal mediation analysis
- Murine sepsis model
Primary result
As reported in the abstract
Endothelial dysfunction markers
PCSK9 LOF influenced Angpt-1, adjusted for confounders incl. lipoproteins (FDR-adjusted p, LDL model)
0.042
PCSK9 LOF influenced Angpt-1, adjusted for confounders incl. lipoproteins (FDR-adjusted p, HDL model)
0.013
Further findings
Mediation of PCSK9 LOF effect on mortality by Angpt-1
- Effect of PCSK9 LOF on mortality mediated by Angpt-1
- P = 0.0008
- Causal mediation analysis
Endothelial markers in juvenile mice with sepsis
- Lower Angpt-1 and higher soluble thrombomodulin in Pcsk9 knockout vs wildtype mice
Original publication
Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1. Crit Care. Published 26 June 2023. doi:10.
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