Genetic variation of TNF is associated with sepsis syndrome and death in severely injured patients

Objectives

Patients encountering severe trauma are at high risk of developing MOF, which is often associated with an unregulated production of mediators of the systemic inflammatory response syndrome [1]. Previous studies suggested an association of TNF and LTA SNPs and the incidence of sepsis among ICU patients [2–4]. By examining several candidate genes (TNF, PAI-1, IL-1, IL-6), previously reported to be associated with sepsis outcome in our cohort [5, 6], we now report that genetic variation in TNF and/or LTA is predictive for the development of sepsis in multiple trauma patients with a low prevalence of other clinically confounding factors.

Patients and methods

One hundred and fifty-nine multiple trauma patients were included prospectively following admission to the ICU with an ISS of 12 points or more after complete assessment of injuries. We genotyped all known SNPs including those in the 5' region of the TNF gene, including LTA, with a reported allele frequency of the rare allele of greater than 5% in Caucasians (n = 9 SNPs). Univariate analysis and multivariate logistic regression analysis were performed.

Results

Seventy-two patients (45.3%) fulfilled the criteria for sepsis after severe trauma and 32 (38.9%) patients died from a sepsis leading to MOF. Allele distributions were according to the HW equilibrium. A significant association for the incidence of sepsis after multiple trauma was observed for the TNF -308A allele (OR 7.14; 95% CI, 3.1–16.45; P < 0.0001), and the completely linked LTA +252G allele (OR 1.96; 95% CI, 1.02–3.78; P < 0.042). Additionally, both alleles showed significant association with death after severe trauma (TNF -308A: OR 7.65; 95% CI, 13.27–17.93; P < 0.0001; LTA +252G: OR 5.58; 95% CI, 2.02–15.44; P < 0.0002).

Conclusion

The presence of one or two copies of the TNF -308A, LTA +252G haplotype is strongly predictive for the incidence of sepsis and death in multiple trauma patients.