title: Genetic variability in complement activation modulates the systemic inflammatory response syndrome in children.
abstract: OBJECTIVE
  To determine the impact of genetic variability in complement activation on early development of the systemic inflammatory response syndrome (SIRS) in general pediatric critical care.
  
  
  METHODS
  Prospective, observational, cohort study.
  
  
  METHODS
  A tertiary pediatric intensive care unit in the United Kingdom.
  
  
  METHODS
  Children with at least one organ failure expected to stay in the intensive care unit >12 hrs, or an expected death within 12 hrs.
  
  
  METHODS
  None.
  
  
  RESULTS
  A total of 299 children were genotyped for functional polymorphisms in the complement activation cascade. We identified complement factor H as an important independent genetic modifier of SIRS/sepsis. Homozygosity for the complement factor H Y402H polymorphism, which is thought to reduce complement inhibition, was associated with less frequent SIRS/sepsis (the adjusted odds ratio for the homozygous variant complement factor H Y402H [CC] carriers was 0.3, 95% confidence interval, 0.1-0.7, p = .005). We also confirmed that structural and promoter variant mannose-binding lectin genotypes are a risk factor for SIRS/sepsis in pediatric critical care (adjusted odds ratio, 2.5; 95% confidence interval, 1.3-5.0, p = .008). Both findings were independent of clinical characteristics and other potentially confounding genetic polymorphisms in the innate immune system.
  
  
  CONCLUSIONS
  Functional polymorphisms in the complement activation cascade modify the risk for early SIRS/sepsis in general pediatric critical care. The complement factor H Y402H variant allele is protective, whereas the mannose-binding lectin variant polymorphisms increase risk. A genotype that permits vigorous complement activation to an infectious or inflammatory insult may offer protection from development of systemic inflammation.
authors.affiliation: Paediatric Intensive Care Unit, Great Ormond Street Hospital NHS Trust, London, United Kingdom. r.agbeko@ich.ucl.ac.uk
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Agbeko
authors.forename: Katy J
authors.initials: KJ
authors.lastname: Fidler
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Allen
authors.forename: Peter
authors.initials: P
authors.lastname: Wilson
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Klein
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Peters
mesh_terms: D003167:Complement Activation; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015278:Intensive Care Units, Pediatric; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics / Q000503:physiopathology*
chemical_list: C493495:CFH protein, human; D037601:Mannose-Binding Lectin; D017242:Complement Factor H