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

Abstract

IntroductionActivation of inflammation and coagulation are closely related and mutually interdependent in sepsis. The acute-phase protein, plasminogen activator inhibitor-1 (PAI-1) is a key element in the inhibition of fibrinolysis. Elevated levels of PAI-1 have been related to worse outcome in pneumonia. We aimed to evaluate the effect of functionally relevant 4G/5G polymorphism of PAI-1 gene in pneumonia induced sepsis.MethodsWe enrolled 208 Caucasian patients with severe sepsis due to pneumonia admitted to an intensive care unit (ICU). Patients were followed up until ICU discharge or death. Clinical data were collected prospectively and the PAI-1 4G/5G polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism technique. Patients were stratified according to the occurrence of multiple organ dysfunction syndrome, septic shock or death.ResultsWe found that carriers of the PAI-1 4G/4G and 4G/5G genotypes have a 2.74-fold higher risk for multiple organ dysfunction syndrome (odds ratio [OR] 95% confidence interval [CI] = 1.335 - 5.604; p = 0.006) and a 2.57-fold higher risk for septic shock (OR 95%CI = 1.180 - 5.615; p = 0.018) than 5G/5G carriers. The multivariate logistic regression analysis adjusted for independent predictors, such as age, nosocomial pneumonia and positive microbiological culture also supported that carriers of the 4G allele have a higher prevalence of multiple organ dysfunction syndrome (adjusted odds ratio [aOR] = 2.957; 95%CI = 1.306 -6.698; p = 0.009) and septic shock (aOR = 2.603; 95%CI = 1.137 - 5.959; p = 0.024). However, genotype and allele analyses have not shown any significant difference regarding mortality in models non-adjusted or adjusted for acute physiology and chronic health evaluation (APACHE) II. Patients bearing the 4G allele had higher disseminated intravascular coagulation (DIC) score at admission (p = 0.007) than 5G/5G carriers. Moreover, in 4G allele carriers the length of ICU stay of non-survivors was longer (p = 0.091), fewer ventilation-free days (p = 0.008) and days without septic shock (p = 0.095) were observed during the first 28 days.ConclusionsIn Caucasian patients with severe sepsis due to pneumonia carriers of the 4G allele of PAI-1 polymorphism have higher risk for multiple organ dysfunction syndrome and septic shock and in agreement they showed more fulminant disease progression based on continuous clinical variables.

Correlation between single nucleotide polymorphisms in hypoxia-related genes and susceptibility to acute high-altitude pulmonary edema

“…Hypoxemia, which functions as a stressor, increases the expression of heat-shock proteins, and protects important organs, such as the lungs and the brain, from harm. Previous studies (Sapru et al, 2009;Madách et al, 2010) have reported a correlation between the 4G/5G polymorphism in the plasminogen activator inhibitor-1 (PAI-1) gene, and the level of expression of pulmonary edema fluid and PAI-1 in the plasma after lung injury. Patients who express the 4G/4G and 4G/5G genotype showed a significant increase in PAI-1 expression; such patients suffered illnesses and inflammatory reactions of greater intensity, and demonstrated obvious pulmonary edema.…”

Гостре Пошкодження Нирок І Тяжка Пневмонія: Сучасна Парадигма Та Клінічні Реалії

“…Решение о начале ЗПТ следует принимать на основе оценки динамики лабораторных данных и всесто-роннего анализа клинической ситуации [19].…”

<i>4G/5G</i> Polymorphism of the Plasminogen Activator Inhibitor-1 Gene Is Associated with Multiple Organ Dysfunction in Critically Ill Patients

“…Also, García-Segarra et al [30] found more severe organ dysfunction in association with higher plasma PAI-1 concentrations and a twofold increase in mortality among patients with septic shock who were homozygous for the 4G deletion polymorphism of PAI-1 . Recently, Madách et al [31] performed a cohort study of 208 Caucasian patients with severe sepsis due to pneumonia and found that those with the 4G/4G and 4G/5G genotypes of PAI-1 had a 2.74-fold higher risk of multiple organ dysfunction syndrome and a 2.57-fold higher risk of septic shock than those with 5G/5G. Multivariate analysis with adjustment for independent predictors (such as age, nosocomial pneumonia and positive culture) also indicated that carriers of the 4G allele had a higher prevalence of multiple organ dysfunction syndrome [31].…”