title: Genetic influence on cytokine production and fatal meningococcal disease.
abstract: BACKGROUND
  To assess the genetic influence on cytokine production and its contribution to fatal outcome, we determined the capacity to produce tumour necrosis factor-alpha (TNF alpha) and interleukin-10 (IL-10) in families of patients who had had meningococcal disease.
  
  
  METHODS
  We studied 190 first-degree relatives of 61 patients with meningococcal disease; we also studied 26 monozygotic twins. Production of cytokines was determined during endotoxin stimulation of whole-blood samples ex-vivo. Heritability was estimated in a pedigree-based maximum-likelihood model. DNA was typed for the G to A transition polymorphisms at position -308 and -238 in the TNF gene promoter.
  
  
  RESULTS
  Heritability in monozygotic twins was 0.60 for the production of TNF and 0.75 for the production of IL-10. Families with low TNF production had a tenfold increased risk for fatal outcome (OR 8.9, 95% CI 1.8-45), whereas high IL-10 production increased the risk 20-fold (19.5, 2.3-165). Families with both characteristics had the greatest risk. The transition polymorphisms in the TNF gene promoter were not associated with outcome.
  
  
  CONCLUSIONS
  Genetic factors substantially influence production of cytokines. An innate anti-inflammatory cytokine profile may contribute to fatal meningococcal disease.
authors.affiliation: Department of Clinical Epidemiology, University Hospital Leiden, Netherlands.
authors.forename: R G
authors.initials: RG
authors.lastname: Westendorp
authors.forename: J A
authors.initials: JA
authors.lastname: Langermans
authors.forename: T W
authors.initials: TW
authors.lastname: Huizinga
authors.forename: A H
authors.initials: AH
authors.lastname: Elouali
authors.forename: C L
authors.initials: CL
authors.lastname: Verweij
authors.forename: D I
authors.initials: DI
authors.lastname: Boomsma
authors.forename: J P
authors.initials: JP
authors.lastname: Vandenbroucke
authors.forename: J P
authors.initials: JP
authors.lastname: Vandenbrouke
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004200:Diseases in Twins; D005260:Female; D006801:Humans; D007223:Infant; D016753:Interleukin-10 / Q000096:biosynthesis*; D008297:Male; D008585:Meningitis, Meningococcal / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D051379:Mice; D008875:Middle Aged; D008957:Models, Genetic; D009345:Neisseria meningitidis / Q000302:isolation & purification; D009679:Nuclear Family; D010375:Pedigree; D011110:Polymorphism, Genetic; D018454:Spouses; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014430:Twins, Monozygotic
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10