Relationship Between Sepsis And A 4G/5G Polymorphism Within The Promoter Region Of Plasminogen Activator Inhibitor-1 (PAI-1) Gene

Plasminogen activator inhibitor 1 (PAI-1) is the most important physiological moduating factor in fibrinolysis system. During fibrinolysis, tissue plasminogen activator (tPA) converts the inactive protein plasminogen into plasmin. Plasmin, in turn, plays a critical role in fibrinolysis by degrading fibrin. PAI-1 is the primary inhibitor of tPA in the blood, which limits the production of plasmin and serves to keep fibrinolysis and coagulation in balance. PAI-1 plays a very important role in sepsis. Increased PAI-1 levels are associated with susceptibility and prognosis of sepsis.The production of PAI-1 was interfered by diverse factors which included cytokins (IL-1/TNF- α a,INF- α ,IFN- γ ), growth factors (TGF- β ,PDGF,IGF-1),insulin, glucocorticoid, lipoprtein, vasopressin II and LPS. These factors act directly on the binding sequence within the promoter region of PA1-1 gene. Genetic polymorphisms, the variations in the promoter, exon, and intron of gene, present as single nucleotide substitution, short tandem repeat, microsatellite, insert or delete of nucleotide. There was a 4G /5G polymorphism -675 bp upstream from the start of transcription. The 4G /5G polymorphism affects PAI-1 transcription and is associated with increased PAI-1 activation.Up to now, there is no study to investigate the relationship between the gene 4G/5G deletion /insertion polymorphism within the promoter of PAI-1 gene and sepsis in Chinese population. It would be helpful to elucidate the contribution of genetic factors to sepsis, and to identify the genetic marker of sepsis, to guide the individual therapy such as APC.ObjectiveTo study whether a 4G/5G polymorphism within the promoter region of plasminogen activator inhibitor-1 (PAI-1) gene is associated with the susceptibility to the incidence of severe sepsis, and contribute to the outcome of sepsis. To elucidate the pathogenesis of sepsis.MethodsEighty-nine patients with severe sepsis and 100 postoperative patients without severe sepsis were enrolled in this study. 4G/5G polymorphism of PAI-1 gene was determined using polymerase chain reaction (PCR) followed by restriction enzyme analysis. The associations between the incidence, outcome of severe sepsis and the allele, genotype of PAJ 4G/5G polymorphism were analysed.ResultsThere was a significant difference in the distribution of genotype and allele frequencies of PAI-1 4G/5G polymorphism between patients with severe sepsis and controls, 0.44 (in sepsis) vs 0.25 (in controls) for 4G/4G genotype distribution, 0.65 (in sepsis) vs 0.50(in controls) for 4G allele frequency, p<0.05. Furthermore, a significant elevation of 4G/4G genotype frequency was observed in the non-survivors comparing with survivors, 0.54 vs 0.34,p<0.05.ConclusionsPAI-1 4G/5G polymorphism is associated with the susceptibility and outcome of severe sepsis, 4G/4G genotype and 4G allele might be a genetic riskfactor of severe sepsis.