A Single Nucleotide Polymorphism in NF-κB Inducing Kinase Is Associated with Mortality in Septic Shock

Abstract

We tested the hypothesis that single nucleotide polymorphisms (SNPs) within genes of the NF-κB pathway are associated with altered clinical outcome of septic shock patients. We genotyped 59 SNPs in the NF-κB pathway in a discovery cohort of septic shock patients (St. Paul’s Hospital [SPH], N = 589), which identified the C allele of rs7222094 T/C within MAP3K14 (NF-κB inducing kinase; NIK) associated with increased 28-d mortality (uncorrected p = 0.00024, Bonferroni corrected p = 0.014). This result was replicated in a second cohort of septic shock patients (Vasopressin and Septic Shock Trial [VASST; N = 616]) in which the CC genotype of rs7222094 was associated with increased 28-d mortality (Cox regression: SPH cohort hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.12–1.64; p = 0.002 Caucasian only; and VASST cohort HR, 1.24; 95% CI, 1.00–1.52; p = 0.048 Caucasian only). Patients having the CC genotype of rs7222094 in SPH experienced more renal and hematological dysfunction (p = 0.003 and p = 0.011), while patients of the VASST cohort with the rs7222094 CC genotype showed the same trend toward more renal dysfunction. In lymphoblastoid cell lines, we found the rs7222094 genotype most strongly associated with mRNA expression of CXCL10, a chemokine regulated by NF-κB. Accordingly, we measured CXCL10 protein levels and found that the CC genotype of rs7222094 was associated with significantly lower levels than those of the TT genotype in lymphoblastoid cell lines (p < 0.05) and in septic shock patients (p = 0.017). This suggests that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients, perhaps due to altered regulation of NF-κB pathway genes, including CXCL10.

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

“…T HERE is wide variability regarding the outcome in severe sepsis, which in part may be caused by genetic variations. [1][2][3] A potential candidate for such variations is the gene encoding nuclear factor-κB and activator protein-1 (NF-κB1), because the ubiquitous transcription factor NF-κB1 binds to recognition elements in the promoter regions of several genes encoding the innate immune and the coagulation system. The nuclear factor-κB family comprises five proteins, NF-κB1, NF-κB2, RelA, RelB, and c-Rel.…”

TNFAIP2 Inhibits Early TNFa-Induced NF-κB Signaling and Decreases Survival in Septic Shock Patients

“…Previous work in our lab and by other study groups has shown that genetic variation within inflammatory genes is associated with outcome in sepsis and septic shock [18][19][20][21][22][23][24][25][26] as well as with the levels of cytokines [27] . We have shown TNFAIP2 inhibits basal NF-κB luciferase activity with a more pronounced effect in the rs8126 G allele.…”

The Meta-Genome of Sepsis: Host Genetics, Pathogens and the Acute Immune Response

“…In the innate immune response, haplotype clades in the integrative inflammatory cytokine IL-6 increase the risk of organ failure and death in those who present with a severe infection [39], while polymorphisms in IL-8, protein C and NFκB-inducing kinase are associated with increased and more severe organ failure complicating septic shock [40,41,42,43]. Because treatment of septic shock is largely supportive, aimed at early broad-spectrum (often nonspecific antibiotics), normalizing blood pressure and organ perfusion [25], polymorphisms in genes active in the vasopressor response are also associated with increased risk of organ dysfunction.…”