RESUMO
Meningococcal disease may present as sepsis, meningitis or a combination of both. Protein C (PC) is an important regulator of thrombin activity. Two polymorphisms in the promoter region of PC (C-1654T, A-1641G) have been shown to affect PC levels. In patients with meningococcal sepsis, low PC levels have been correlated with increased severity and poor outcome. We established a multicenter case-control study to determine whether PC promoter polymorphisms are associated with occurrence and outcome of meningococcal disease and sepsis. 288 previously healthy children with meningococcal infection from 97 pediatric hospitals in Germany, Switzerland, Italy, and Austria and 309 healthy controls were included in the study. A strong age-dependant effect was found. Patients younger than 1 year carried significantly more often the CG-CG genotype than healthy controls (28.6% vs. 17.8%, P = 0.04). Carriers of the CG allele showed a 3.43-fold increased odds ratio (OR) to develop sepsis (95% CI: 1.05-11.20; 85.7% vs. 63.6%, P = 0.036). The TA-TA genotype conferred a protective role for the development of sepsis (P = 0.017) with a Haldane OR of 0.09 (95% CI: 0.01-0.94). Systolic blood pressure values were significantly decreased in patients carrying the CG-CG genotype (70 vs. 86 mmHg, P = 0.005), and the need for adrenergic support significantly higher (70% vs. 26%, P = 0.018), resulting in an OR of 6.61 (95% CI: 1.28-34.14). These findings show that in young children PC promoter genotype is associated with susceptibility for meningococcal disease, the development of meningococcal sepsis, lower blood pressure, and need for adrenergic support.
Assuntos
Infecções Meningocócicas/complicações , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Proteína C/genética , Sepse/etiologia , Sepse/genética , Adolescente , Fatores Etários , Pressão Sanguínea , Criança , Pré-Escolar , Primers do DNA/genética , Europa (Continente) , Frequência do Gene , Genótipo , Humanos , Lactente , Recém-Nascido , Razão de ChancesRESUMO
BACKGROUND: An association has been described between mortality in children with meningococcal disease and functional polymorphisms in the interleukin-1 (IL1) cluster. We undertook a multicenter study to evaluate associations of these polymorphisms in a Central European population. PATIENTS AND METHODS: The study involved 95 Middle European pediatric hospitals. We collected blood samples from, and clinical information about, 285 previously healthy children with meningococcal infection. We used a newly developed multiplexed mutagenic separated PCR assay to analyze 6 polymorphisms within the IL1 cluster: IL1A (-889)C/T, IL1A (+4845)G/T, IL1B (-511)C/T, IL1B (-31)C/T, IL1B (+3954), and IL1RA (+2018)C/T. We studied the same polymorphisms in a comparison group of 481 healthy newborns. RESULTS: Genotype frequencies between patients and the comparison group differed significantly only for the IL1RA (+2018)C/T variant: The CC genotype was more frequent in patients (11%) than in healthy controls (5%; P = 0.008). In the patient group, the C allele was significantly more prevalent (67%) in nonsurvivors than in survivors (42%; P = 0.02). CONCLUSION: The IL1RA (+2018)C/T polymorphism is associated with the risk of meningococcal disease and with its outcome.
Assuntos
Interleucina-1/genética , Infecções Meningocócicas/imunologia , Família Multigênica , Polimorfismo Genético , Adolescente , Adulto , Criança , Pré-Escolar , Europa (Continente) , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Infecções Meningocócicas/genética , População BrancaRESUMO
UNLABELLED: Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor-1 (PAI-1) is a characteristic feature of meningococcal sepsis. Previously, an association between mortality and the functional 4G/5G promoter polymorphism of the PAI-1gene in a cohort of UK and Dutch children with meningococcal sepsis was reported. We carried out a prospective, multicentre study to investigate the association of the 4G/5G PAI-1 polymorphism, diagnosis, and outcome in meningococcal disease in a Central European and UK population. Blood samples and clinical information of 347 previously healthy children with meningococcal infection were collected from 95 paediatric hospitals in Germany, Switzerland, Italy, the United Kingdom, and Austria from 2000 until 2002. Mortality was significantly associated with the 4G/4G genotype (12 of 90 (13%) vs. 15 of 240 (6%), P = 0.037), resulting in an odds ratio of 2.31. The diagnosis of sepsis (independent of symptoms of meningitis) was significantly more frequent in carriers of the 4G/4G genotype (P = 0.01), resulting in an odds ratio of 2.21 to develop sepsis. Meningitis was not associated with the PAI-1 4G/5G polymorphism, and allele frequencies were similar in patient and control groups. CONCLUSION: Our data show a correlation between the 4G/4G genotype in the plasminogen activator inhibitor-1 gene and poor outcome in children with meningococcal infection. In addition, 4G homozygous patients were prone to develop sepsis. We found no influence of the plasminogen activator inhibitor-1 polymorphism on the susceptibility to invasive meningococcal infection.