4G/5G polymorphism of PAI-1 gene is associated with multiple organ dysfunction and septic shock in pneumonia induced severe sepsis: prospective, observational, genetic study

摘要

Introduction: Activation of inflammation and coagulation are udclosely related and mutually interdependent in sepsis. The udacute-phase protein, plasminogen activator inhibitor-1 (PAI-1) udis a key element in the inhibition of fibrinolysis. Elevated udlevels of PAI-1 have been related to worse outcome in pneumonia. udWe aimed to evaluate the effect of functionally relevant 4G/5G udpolymorphism of PAI-1 gene in pneumonia induced sepsis. Methods: udWe enrolled 208 Caucasian patients with severe sepsis due to udpneumonia admitted to an intensive care unit (ICU). Patients udwere followed up until ICU discharge or death. Clinical data udwere collected prospectively and the PAI-1 4G/5G polymorphism udwas genotyped by polymerase chain reaction-restriction fragment udlength polymorphism technique. Patients were stratified udaccording to the occurrence of multiple organ dysfunction udsyndrome, septic shock or death. Results: We found that carriers udof the PAI-1 4G/4G and 4G/5G genotypes have a 2.74-fold higher udrisk for multiple organ dysfunction syndrome (odds ratio [OR] ud95% confidence interval [CI] = 1.335 -5.604; p = 0.006) and a ud2.57-fold higher risk for septic shock (OR 95% CI = 1.180 - ud5.615; p = 0.018) than 5G/5G carriers. The multivariate logistic udregression analysis adjusted for independent predictors, such as udage, nosocomial pneumonia and positive microbiological culture udalso supported that carriers of the 4G allele have a higher udprevalence of multiple organ dysfunction syndrome (adjusted odds udratio [aOR] = 2.957; 95% CI = 1.306 -6.698; p = 0.009) and udseptic shock (aOR = 2.603; 95% CI = 1.137 - 5.959; p = 0.024). udHowever, genotype and allele analyses have not shown any udsignificant difference regarding mortality in models non-udadjusted or adjusted for acute physiology and chronic health udevaluation (APACHE) II. Patients bearing the 4G allele had udhigher disseminated intravascular coagulation (DIC) score at udadmission (p = 0.007) than 5G/5G carriers. Moreover, in 4G udallele carriers the length of ICU stay of non-survivors was udlonger (p = 0.091), fewer ventilation-free days (p = 0.008) and uddays without septic shock (p = 0.095) were observed during the udfirst 28 days. Conclusions: In Caucasian patients with severe udsepsis due to pneumonia carriers of the 4G allele of PAI-1 udpolymorphism have higher risk for multiple organ dysfunction udsyndrome and septic shock and in agreement they showed more udfulminant disease progression based on continuous clinical udvariables.