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Intravenous Endotoxin Challenge in Healthy Humans: An Experimental Platform to Investigate and Modulate Systemic Inflammation
Published on: May 16, 2016
Genetic variability in complement activation modulates the systemic inflammatory response syndrome in children.
Rachel S Agbeko1, Katy J Fidler, Meredith L Allen
1Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Trust, London, United Kingdom. r.agbeko@ich.ucl.ac.uk
Summary
Genetic variations in complement activation impact systemic inflammatory response syndrome (SIRS) in critically ill children. Certain complement factor H variants protect against SIRS, while mannose-binding lectin variants increase risk.
Area of Science:
- Immunogenetics
- Pediatric Critical Care
- Systemic Inflammation
Background:
- The complement system plays a crucial role in innate immunity and inflammation.
- Genetic variability in complement pathways may influence susceptibility to severe inflammatory conditions like SIRS.
- Understanding these genetic factors is vital for predicting and managing SIRS in pediatric intensive care.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in complement activation and the early development of SIRS in pediatric critical care.
- To identify specific complement genes that act as modifiers of SIRS risk in children.
Main Methods:
- Prospective observational cohort study conducted in a UK tertiary pediatric intensive care unit.
- Genotyping of 299 children for functional polymorphisms in the complement activation cascade.
- Analysis of genetic variants, including complement factor H (CFH) and mannose-binding lectin (MBL), in relation to SIRS development.
Main Results:
- Complement factor H (CFH) was identified as a significant genetic modifier of SIRS/sepsis.
- Homozygosity for the CFH Y402H polymorphism was associated with a reduced risk of SIRS/sepsis (OR 0.3, p=0.005).
- Mannose-binding lectin (MBL) genotypes were confirmed as a risk factor for SIRS/sepsis (OR 2.5, p=0.008), independent of clinical factors.
Conclusions:
- Functional polymorphisms in complement activation pathways significantly modify SIRS/sepsis risk in pediatric critical care.
- The CFH Y402H variant allele appears protective against SIRS, whereas MBL variant polymorphisms increase risk.
- Vigorous complement activation, influenced by specific genotypes, may confer protection against systemic inflammation.
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