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

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 greater than or equal to 20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma ( injury severity score (ISS)greater than or equal to 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 - 159) and inflammatory response (TNF-alpha 2308, IL-1beta-31, IL-6 -174) 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-alpha -308 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-alpha -308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.