4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease

Background Intravascular coagulation with infarction of skin, digits, and l imbs is a characteristic feature of meningococcal sepsis. Children with men ingococcal sepsis have higher than normal concentrations of plasminogen act ivator inhibitor 1 (PAI-1) in plasma. Combined with the widespread venous t hrombosis, this finding suggests an impairment of fibrinolysis. A common fu nctional insertion/deletion (4G/5G) polymorphism exists in the promoter reg ion of the PAI-1. gene. We tested the hypothesis that children with the 4G/ 4G genotype produce higher concentrations of PAI-1, develop more severe coa gulopathy, and are at greater risk of death during meningococcal sepsis. Methods The relation between meningococcal disease outcome, PAI-1 concentra tion, ana PAI-1 genotype was investigated in 175 children with meningococca l disease (37 from Rotterdam, the Netherlands, and 138 from London, UK) and 226 controls (137 from Rotterdam, 89 from London). PAI-1 concentrations in plasma were measured by ELISA, and the 4G/5G PAI-1 polymorphism was detect ed by PCR and hybridisation. Findings Concentrations of PAI-1 on admission correlated with presentation (sepsis or meningitis) and outcome. The median PAI-1 concentration in child ren who died was substantially higher than that in survivors (2448 [IQR 111 5-3191] vs 370 [146-914] ng/mL; p<0.0001). Patients with the 4G/4G genotype had significantly higher PAI-1 concentrations than those with the 4G/5G or 5G/5G genotype (1051 [550-2440] vs 436 [198-1225] ng/mL; p=0.03), and had an increased risk of death (relative risk 2.0 [1.0-3.8] for the two cohorts combined, and 4.8 [1.8-13] for the London cohort). Interpretation A genetic predisposition to produce high concentrations of P AI-1 is associated with poor outcome of meningococcal sepsis. This finding suggests that impaired fibrinolysis is an important factor in the pathophys iology of meningococcal sepsis.