TLR4 and TNF-  polymorphisms are associated with an increased risk for severe sepsis following burn injury

Abstract

Context: Sepsis, organ failure, and shock remain common among patients with moderate to severe burn injuries. The inability of clinical factors to identify at-risk patients suggests that genetic variation may influence the risk for serious infection and the outcome from severe injury. Objective: Resolution of genetic variants associated with severe sepsis following burn injury. Patients: A total of 159 patients with burns >20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)>16), traumatic or anoxic brain injury, or spinal cord injury and who survived more than 48 h post-admission. Methods: Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 2159) and inflammatory response (TNF-a 2308, IL-1b 231, IL-6 2174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality. Results: After adjustment for age, full-thickness burn size, ethnicity, and gender, carriage of the TLR4 +896 G-allele imparted at least a 1.8-fold increased risk of developing severe sepsis following a burn injury, relative to AA homozygotes (adjusted odds ratio (aOR) 6.4; 95% confidence interval (CI) 1.8 to 23.2). Carriage of the TNF-a 2308 A-allele imparted a similarly increased risk, relative to GG homozygotes (aOR = 4.5; 95% CI 1.7 to 12.0). None of the SNPs examined were significantly associated with mortality. Conclusions: The TLR4 +896 and TNF-a 2308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

Characteristics of Burn Injury and Factors in Relation to Infection among Pediatric Patients

“…Carriers of the G-allele at this single nucleotide polymorphism (SNP) exhibit reduced lipopolysaccharide (LPS) responsiveness as well as an increased risk for septic shock and susceptibility to Gram-negative sepsis. 77 In the present study, we found that the higher incidence of gramnegative bacteria statistically significant with more prolonged hospital stays p<0.001 (Table 10). Inanimate environment of patient infected with gram-negative bacteria was frequently contaminated with those organisms considered a factor for infection.…”

Incremental expression of Tlr4 correlates with mouse resistance to Salmonella infection and fine regulation of relevant immune genes

“…36 On the other hand, the same alleles have shown protective effects against various diseases such as atherosclerosis, 37 Legionnaire's disease 38 and late-onset Alzheimer's disease. 39 In light of these findings, the mice characterized in the present study could represent invaluable tools to study in more depth the role of slightly different levels of Tlr4 expression in specific diseases outcome and pathophysiology.…”

Impaired TLR5 Functionality Is Associated with Survival in Melioidosis

“…We chose two coding variants, one in TLR4 and one in TIRAP, to analyze in this population: TLR4 896A.G (rs4986790) and TIRAP 558C.T (rs7932766). Both variants have been previously associated with infection, with functional effects demonstrated by some authors (19)(20)(21)(22)(23)(24). We have shown that the TLR4 896A.G variant is rare in Thais (MAF , 1%) (13)…”