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.
As judged from the pattern of soluble cytokines in plasma and the effect of the plasma on monocyte activation by LPS, mild, localized infection can induce a systemic response that is predominantly anti-inflammatory.
Genetic variations contribute to differences in the inflammatory response and are markers for disease risk and outcomes. We studied three single-nucleotide polymorphisms (-597 G-->A, -572 G-->C, and -174 G-->C) in the IL-6 promoter to determine associations with ex vivo LPS-stimulated IL-6 production by leukocytes. We also measured nuclear protein binding to synthetic oligonucleotides representing the -174 polymorphic region, located in proximity to important transcription factor motifs. We determined genotypes at three sites in the IL-6 promoter by pyrosequencing of genomic DNA obtained from 49 healthy control subjects. To determine molecular haplotypes, cloned DNA fragments from heterozygous subjects were sequenced. IL-6 release by whole blood leukocytes was measured after 24 h of ex vivo LPS stimulation. We compared IL-6 concentrations between haplotypes using Kruskall-Wallis and adjusted for covariates by analysis of covariance. Electromobility gel shift assay was carried out by the incubation of nuclear proteins from cultured human mononuclear cells with oligonucleotides representing the alternate -174 alleles. The amount of nuclear protein binding was quantified by densitometry, which was compared using analysis of variance. Genotype and sequence analysis of genomic and cloned DNA characterized three haplotypes. Ex vivo IL-6 production was greatest in individuals who were homozygous for the haplotype containing guanine at -597 and -174. IL-6 production was least for individuals homozygous for the haplotype containing adenine at -597 and cytosine at -174. Nuclear protein bound more avidly to guanine-containing oligonucleotides representing the -174 position than to oligonucleotides containing cytosine at that position. The IL-6 promoter haplotype influences ex vivo IL-6 response to endotoxin. This effect may be due to a functional effect of the -174 G-->C polymorphism.
Polymorphism in the IL-6 gene was associated with the severity of appendicitis, even after adjustment for duration of symptoms. The risk for developing appendiceal perforation or gangrene may be determined, in part, by variation in the IL-6 gene.
The development of effective inhibitors of p38 and JNK protein mediators is important for minimizing the harmful effects associated with liver ischemia and reperfusion.
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