The discovery of functional single nucleotide polymorphisms and novel gene mechanisms that may explain mortality and organ dysfunction in septic shock

Septic shock (sepsis accompanied by cardiovascular failure) is an extreme manifestation of the host inflammatory response to severe infection. Tumor necrosis factor alpha (TNFα) super family induced nuclear factor kappa B (NF-κB) signaling pathways play a critical role in the pathophysiology of the disease. A better understanding of how TNFα induced NF-κB signaling influences the pathogenesis of septic shock is imperative. NF-κB signaling is activated by a canonical pathway or a non-canonical pathway. The canonical NF-κB pathway requires the IκB kinase (IKK) complex comprised of IKKα/β/γ. Activation of the IKK complex in response to inflammatory stimuli, such as TNFα, results in ubiquitin-dependent degradation of IκBα or IκBβ, releasing p50 related dimers to the nucleus. In response to TNFα superfamily induced inflammation in the non-canonical pathway, NF-κB inducing kinase (NIK), a docking molecule, recruits IΚΚα to p100 thus activating IΚΚα. This phosphorylates p100, which is then degraded, releasing p52 containing RelB heterodimers to the nucleus. It has been shown that genetic variation in key inflammatory genes contributes to outcome in sepsis. We hypothesized that genetic variation in genes of TNFα super family induced NF- κB signaling would be associated with mortality in septic shock. Specifically, we first tested the hypothesis that genetic variation within the cytosolic members of the canonical and noncanonical pathway may be associated with mortality in septic shock. We found that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients. This is perhaps due to altered regulation of NF-κB pathway genes, including CXCL10. We then tested the hypothesis that genetic variation in genes upregulated by these pathways may be associated with mortality in septic shock. We showed that the G allele of TNFAIP2 rs8126 is associated with increased mortality and organ dysfunction in septic shock patients. We then elucidated a novel biological mechanism whereby TNFAIP2 is a novel inhibitor of Ras, CREB and NF-κB; TNFAIP2 levels are controlled by rs8126; and these by allele differences are reflected in the inhibiton of Ras, CREB and NF-κB.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat