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Infection risk and mortality after burn trauma are primarily determined by patient age, burn size and depth, and associated inhalation injury. Whether genetic differences contribute to otherwise unexpected variability in outcomes is unknown. We sought to determine whether there was an association between genetic variation in inflammation-related genes and outcomes after burn trauma. We evaluated patients with burns ≥15% TBSA at a single regional burn center from October 2003 to December 2005. Blood was collected on admission and DNA genotyping was performed. We genotyped single nucleotide polymorphism (SNPs) in toll-like receptor 4 (TLR4) A896G, tumor necrosis factor alpha (TNF-α) G-308A, Interleukin-6 (IL-6) G-174C, interleukin-1β (IL-1β) T-31C, and cluster of differentiation marker 14 (CD14) C-159T. We compared SNP genotypes between survivors and nonsurvivors by χ2 analysis and logistic regression. Sixty-nine subjects with a median age of 38 years and mean TBSA of 34% were enrolled. The case fatality was 17%. Septic shock developed in 7 (10%) patients. After adjustment for age, percent full-thickness burns, and inhalation injury, carriage of the TNF-α −308 variant allele was associated with increased risk of mortality (OR 10.7, 95% CI = 1.2–95.5, P = .034). None of the other SNPs evaluated were associated with mortality. Mortality after burn trauma is primarily determined by clinical factors, but the TNF-α −308 A allele seems to contribute to an increased mortality risk.