Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock

Background. Some patients infected with Neisseria meningitidis develop septic shock accompanied by fibrin deposition and microthrombus formation in various organs, whereas others develop bacteraemia or meningitis without septic shock. We investigated whether genetic differences in the fibrinolytic system influence the development of meningococcal septic shock. Methods. We investigated 50 patients who survived meningococcal infection, and 131 controls from the same geographical region. Because we had no information on genotypes of patients who died, we also genotyped 183 first-degree relatives of a consecutive series of patients with meningococcal infection for the 4G/5G deletion/insertion polymorphism in the promoter region of the plasminogen-activator-inhibitor-1 gene (PAI-1). The 4G allele is associated with increased gene transcription in cell lines in vitro and with increased PAI-1 concentrations in carriers in vivo. Findings. The allele frequencies of 4G and 5G were similar between patients and controls. However, the 4G/4G genotype was present in only 9% of relatives of patients with meningitis compared with 36% of relatives of patients with septic shock. The 5G/5G genotype was more common among relatives of patients with meningitis (31 vs 11%, p = 0.001). Patients whose relatives were carriers of the 4G/4G genotype had a six-fold higher risk of developing septic shock than meningitis (odds ratio 5.9 [95% CI 1.9-18.0]) compared with all other genotypes. Interpretation. Variation in the PAI-1 gene does not affect the probability of contracting meningococcal infection, but does influence the development of septic shock.