4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group.
BACKGROUND
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.


METHODS
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.


RESULTS
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<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).


CONCLUSIONS
A genetic predisposition to produce high concentrations of PAI-1 is associated with poor outcome of meningococcal sepsis. This finding suggests that impaired fibrinolysis is an important factor in the pathophysiology of meningococcal sepsis.
Hermans
P W
PW
Department of Paediatrics, Sophia Children's Hospital, Erasmus University Rotterdam, The Netherlands. hermans@kgk.fgg.eur.nl
Hibberd
M L
ML
Booy
R
R
Daramola
O
O
Hazelzet
J A
JA
de Groot
R
R
Levin
M
M
D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004211:Disseminated Intravascular Coagulation / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D007223:Infant; D008131:London / Q000453:epidemiology; D008297:Male; D008589:Meningococcal Infections / Q000150:complications / Q000235:genetics* / Q000401:mortality; D009426:Netherlands / Q000453:epidemiology; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012307:Risk Factors
D017395:Plasminogen Activator Inhibitor 1