Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children.
OBJECTIVE
Meningococcal sepsis invariably is associated with coagulopathy. We have previously reported an association between mortality rate in meningococcal disease and the functional 4G/5G promoter polymorphism of the plasminogen-activator-inhibitor (PAI)-1 gene in a small patient cohort. In a much larger cohort, we aimed to confirm these results and further investigate the role of the 4G/5G polymorphism in determining susceptibility, outcome, and complications of disease.DESIGN Susceptibility was investigated in two separate studies, a case-control study and a family-based transmission study, each test using a separate patient cohort. Severity was investigated using clinical diagnosis, the presence of vascular complications, Pediatric Risk of Mortality (PRISM)-predicted morality, and actual mortality.


METHODS
University hospital and laboratories.


METHODS
Subjects were 510 UK pediatric patients, 210 parents of patients, and 155 UK Caucasian controls.


METHODS
DNA extraction and 4G/5G PAI-1 genotyping was carried out using published techniques.


RESULTS
Predicted mortality distribution differed significantly between genotypes (p =.05) with a significantly higher median PRISM in the 4G/4G (41.1%) than the 4G/5G (23.4%) and 5G/5G (19.0%) genotyped patients combined (p =.02). Actual mortality rate was significantly associated with both genotype (chi-square = 14.8, p =.001) and allele frequencies (chi-square = 14.0, p <.0001), with more deaths in the 4G/4G (28.4%) than the 4G/5G and 5G/5G genotyped patients combined (14.9%; chi-square = 7.9; p =.005; risk ratio, 1.9; 95% confidence interval, 1.2-3.0). Logistic regression indicated a 40% and 91% reduction in the odds of dying if a patient was either 4G/5G or 5G/5G, respectively, in comparison to a 4G homozygous patient. When analyzed by clinical diagnosis, the association with death was found only in the sepsis group (chi-square = 18.7, p <.0001; risk ratio, 2.7; 95% confidence interval, 1.6-4.6). In survivors of disease, a significantly higher proportion of 4G/4G patients suffered from vascular complications (chi-square = 6.7, p =.03; risk ratio, 2.4; 95% confidence interval, 1.1-5.0). The 4G/5G polymorphism was not associated or linked with susceptibility (case-control result, p =.6; family-based transmission study results, p =.2).


CONCLUSIONS
This study confirms that Caucasian pediatric patients carrying the functional PAI-1 4G/4G genotype are at an increased risk of developing vascular complications and dying from meningococcal disease.
Haralambous
Elene
E
Faculty of Medicine, Imperial College London, UK. e.haramboous@ic.ac.uk
Hibberd
Martin L
ML
Hermans
Peter W M
PW
Ninis
Nelly
N
Nadel
Simon
S
Levin
Michael
M
D000293:Adolescent; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008589:Meningococcal Infections / Q000150:complications / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D010375:Pedigree; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics*
D017395:Plasminogen Activator Inhibitor 1