RESUMO
OBJECTIVES: Excessive inflammation is closely related to severity and outcome of sepsis. Because interleukin-1-receptor-associated kinase 1 is a key signaling protein in the activation of NF-κB during infection, we aimed to evaluate the effect of functionally relevant haplotypes of IRAK1 on severity, development of acute lung injury, and mortality in septic shock. DESIGN: Prospective, observational, cohort study. SETTING: Three medical intensive care units in three French university hospitals. PATIENTS: Eight hundred forty-three Caucasian patients with septic shock and 800 sex-matched Caucasian control subjects were enrolled. INTERVENTIONS: Patients were genotyped for the IRAK1-1595C/T polymorphism, which tagged the IRAK1 functional haplotype. MEASUREMENTS AND MAIN RESULTS: No significant differences in IRAK1 genotypes were seen between patients and control subjects. Among the septic shock group, the IRAK1 variant haplotype was significantly associated with the need for prolonged mechanical ventilation (p=.02). In a prespecified subgroup, this genetic risk was most severe in the youngest patients (age<65 yrs, p=.005). Furthermore, in the more severe subgroup of patients, a higher mortality rate was found in patients carrying the IRAK-1 variant haplotype as compared with the wild type (p=.02) (odds ratio, 2.1; 95% confidence interval, 1.1-4.8). CONCLUSIONS: The IRAK1 variant haplotype is associated with prolonged ventilation in septic shock. In the future, the IRAK1-1595C/T polymorphism might be included in scores such as PIRO (predisposition, insult, response, and organ dysfunction) to adapt preventive and therapeutic interventions in the intensive care unit.
Assuntos
Predisposição Genética para Doença , Variação Genética , Quinases Associadas a Receptores de Interleucina-1/genética , Polimorfismo Genético , Choque Séptico/genética , APACHE , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Regulação da Expressão Gênica , Marcadores Genéticos , Haplótipos , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Estudos Prospectivos , Valores de Referência , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Choque Séptico/mortalidade , Choque Séptico/terapiaRESUMO
BACKGROUND: Matrix metalloproteinases (MMPs) may contribute to endometriosis. We tested whether eight functional polymorphisms of these genes could modify the risk of endometriosis. METHODS: In this case-control study, 227 endometriosis and 241 controls were genotyped for MMP1 -1607 1G/2G, MMP2 -1575 G/A (MMP2.1), -1306 C/T (MMP2.2), MMP3 -1612 5A/6A, MMP7 -153 C/T (MMP7.1), -181 A/G (MMP7.2), MMP12 -82 A/G and MMP13-77 A/G. Association between MMP genotypes and superficial (SUP), deep infiltrating (DIE) and endometriomas (OMA) was tested for each polymorphism separately, using unconditional logistic regression and then for combined genotypes, using the combination test. RESULTS: When considering all cases, MMP2 polymorphisms were found to be significant, mainly due to DIE (P = 0.023). A small difference between SUP and controls was found for MMP7.2 (P = 0.032) and MMP12 (P = 0.035), in the absence of correction for multiple testing. Using the combination test, the best association when comparing SUP with controls was obtained for MMP12-MMP13 (P = 0.004) for the combined genotype A/G-A/A (odds ratio = 27.60, 95% confidence interval: 2.80-272.40). CONCLUSIONS: These data show a potential role for MMP12 -82 A/G and MMP13 -77 A/G combined polymorphisms in superficial endometriosis. As no association was found with deep infiltrating endometriosis, this combination of polymorphisms might protect from a more in-depth penetration of tissues.
