GENETIC INFLUENCE ON CYTOKINE PRODUCTION AND FATAL MENINGOCOCCAL DISEASE

Background To assess the genetic influence on cytokine production and its contribution to fatal outcome, we determined the capacity to produ ce 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-likeliho od model. DNA was typed for the G to A transition polymorphisms at pos ition -308 and -238 in the TNF gene promoter. Findings 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 tenfo ld increased risk for fatal outcome (OR 8 . 9, 95% Cl 1 . 8-45), where as high IL-10 production increased the risk 20-fold (19 . 5, 2 . 3-165 ). Families with both characteristics had the greatest risk. The trans ition polymorphisms in the TNF gene promoter were not associated with outcome. Interpretation Genetic factors substantially influence produc tion of cytokines. An innate anti-inflammatory cytokine profile may co ntribute to fatal meningococcal disease.