Role of functional plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism in susceptibility, severity, and outcome of meningococcal disease in Caucasian children.
Crit Care Med
; 31(12): 2788-93, 2003 Dec.
Article
in En
| MEDLINE
| ID: mdl-14668616
ABSTRACT
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.SETTING:
University hospital and laboratories.SUBJECTS:
Subjects were 510 UK pediatric patients, 210 parents of patients, and 155 UK Caucasian controls.INTERVENTIONS:
DNA extraction and 4G/5G PAI-1 genotyping was carried out using published techniques. MEASUREMENTS AND MAINRESULTS:
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Polymorphism, Genetic
/
Promoter Regions, Genetic
/
Plasminogen Activator Inhibitor 1
/
Genetic Predisposition to Disease
/
White People
/
Meningococcal Infections
Type of study:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Adolescent
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Country/Region as subject:
Europa
Language:
En
Journal:
Crit Care Med
Year:
2003
Document type:
Article
Affiliation country:
Reino Unido