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

• Published in: The Lancet (British edition) 1999-08, Vol.354 (9178), p.556-560
• Main Authors: Hermans, Peter WM, Hibberd, Martin L, Booy, Robert, Daramola, Olufunmilayo, Hazelzet, Jan A, de Groot, Ronald, Levin, Michael
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Children & youth; Emergency and intensive care: infection, septic shock; Genes; Intensive care medicine; Medical research; Medical sciences; Meningitis; Thromboembolism
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(99)02220-5

Intravascular coagulation with infarction of skin, digits, and limbs is a characteristic feature of meningococcal sepsis. Children with meningococcal sepsis have higher than normal concentrations of plasminogen activator inhibitor 1 (PAI-1) in plasma. Combined with the widespread venous thrombosis, this finding suggests an impairment of fibrinolysis. A common functional insertion/deletion (4G/5G) polymorphism exists in the promoter region 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 coagulopathy, and are at greater risk of death during meningococcal sepsis. The relation between meningococcal disease outcome, PAI-1 concentration, and PAI-1 genotype was investigated in 175 children with meningococcal 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 detected by PCR and hybridisation. Concentrations of PAI-1 on admission correlated with presentation (sepsis or meningitis) and outcome. The median PAI-1 concentration in children who died was substantially higher than that in survivors (2448 [IQR 1115–3191] vs 370 [146–914] ng/mL; p