A common haplotype of the LBP gene predisposes to severe sepsis

Objective: To investigate whether common variants across the LBP gene contribute to the development of severe sepsis. Sepsis is the leading cause of multiple system organ dysfunction and death in critically ill patients. The lipopolysaccharide-binding protein is an acute-phase protein that plays a dominant role in the genesis of sepsis by initiating signal transduction pathways leading to the activation of the inflammatory host response. Design: Prospectively enrolled case-control study of adults with severe sepsis. Setting: A network of intensive care units. Patients: We enrolled 175 patients meeting international definition criteria for severe sepsis and 357 population-based controls for comparison. Interventions: Genotyping of the LBP gene was performed and disease association was tested. Serum lipopolysaccharide-binding protein levels were measured in patients and related to genetic variants. Measurements and Main Results: A haplotype window analysis revealed that a common 4-SNP risk haplotype from the 5′-flanking region of the LBP gene, comprising positions -1978 to -763 from the transcription start site, was strongly associated with susceptibility to severe sepsis. Risk haplotype homozygous carriers had an increased risk for severe sepsis (odds ratio = 2.21; 95% confidence interval = 1.39-3.51; unadjusted p < .001; adjusted p < .025). Mean serum lipopolysaccharide-binding protein levels from inclusion to 7 day were significantly higher in homozygous carriers patients (130.1 [102.9-164.5] and 98.9 [79.7-122.8] μg/mL, respectively) than in noncarriers (101.6 [87.9-117.5] and 58.7 [51.4-67.2] μg/mL, respectively) (p = .046). Conclusions: This study strongly supports the involvement of LBP gene variants in severe sepsis susceptibility and reinforces the merit of further exploration of the role of lipopolysaccharide-binding protein in sepsis.