The NFKB1 Promoter Polymorphism (-94ins/delATTG) Alters Nuclear Translocation of NF-κB1 in Monocytes after Lipopolysaccharide Stimulation and Is Associated with Increased Mortality in Sepsis

Background: Because the nuclear factor-kappa B (NF-kappa B) coupled pathway is believed to amplify inflammation prevailing in sepsis, the authors tested the hypotheses that the insertion-deletion polymorphism (-94ins/delATTG) (1) alters nuclear translocation of nuclear factor-kappa B and activator protein-1 (NF-kappa B1) in monocytes after lipopolysaccharide stimulation; (2) affects lipopolysaccharide-induced NF-kappa B1 messenger RNA expression, tumor necrosis factor a concentrations, and tissue factor activity; and (3) may be associated with increased 30-day mortality in patients with sepsis. Methods: Nuclear translocation of NF-kappa B1 in monocytes after lipopolysaccharide stimulation from healthy blood donors was performed with immunofluorescence staining (n = 5 each). Lipopolysaccharide-induced NF-kappa B1 messenger RNA expression was measured with real-time polymerase chain reaction (PCR; n = 60), tumor necrosis factor a concentrations with a multiplexing system kit (n = 60), and tissue factor activity with thromboelastometry (n = 105). In a prospective study, multivariate proportional hazard analysis tested 30-day mortality in patients with sepsis (n = 143). Methods and Results: The homozygous deletion genotype compared with the homozygous insertion genotype was associated with a nearly twofold increase in nuclear translocation of NF-kappa B1 (P = 0.001), a threefold difference in NF-kappa B1 messenger RNA expression (P = 0.001), and a twofold increase in tissue factor expression (P = 0.021). The deletion allele in adults with severe sepsis was tested as an independent prognostic factor for 30-day mortality (hazard ratio, 2.3; 95% CI, 1.13-4.8; P = 0.022). Mortality was 25% for homozygous insertion genotypes but 41% for combined heterozygous deletion/homozygous deletion genotypes ( P = 0.034). Conclusion: The deletion allele of the NF kappa B1 insertion-deletion (-94ins/delATTG) polymorphism is associated with increased 30-day mortality in patients with severe sepsis and increased reaction of the innate immune system.