Tumor necrosis factor -308 polymorphism (rs1800629) is associated with mortality and ventilator duration in 1057 Caucasian patients

Purpose: Management of sepsis in critically ill patients remains difficult and requires prolonged intensive care. Genetic testing has been proposed as a strategy to identify patients at risk for adverse outcome of critical illnesses. Therefore, we wished to determine the influence of heredity on predisposition to poor outcome and on duration of ventilator support of intensive care unit (ICU) patients. Methods: A study was conducted from July 2001 to December 2005 in heterogeneous population of patients from 12 US ICUs represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive. In 1057 Caucasian critically ill patients with SAPS II probability of survival of >0.2 in the US, six functional single nucleotide polymorphisms in relation to inflammatory cytokines and innate immunity (rs1800629, rs16944, rs1800795, rs1800871, rs2569190, and rs909253) were evaluated in terms of mortality and ventilator free days. Results: The AA homozygote of TNF(-308) (rs1800629) was most over-represented in the deceased patient group (P=0.015 with recessive model). The carriage of the TNF(-308)*AA genotype showed significantly higher odds ratio of 2.67(1.29-5.55) (P=0.008) after adjustment with the covariates. However, the presence of 1, 2, or 3 acute organ dysfunctions was larger prognostic factors for the adverse outcome (OR(95%CI)=2.98(2.00-4.45), 4.01(2.07-7.77), or 19.95(4.99-79.72), P<0.001 for all). Kaplan-Mayer plot on ventilator duration of TNF(-308)*AA patient significantly diverged from that of TNF(-308)*(GG. +. GA) ((AA v GG. +. GA), Adjusted HR(95%CI)=2.53(1.11-5.79) with Cox regression, P=0.028). Conclusions: TNF(-308)*AA is significantly associated with susceptibility to adverse outcome and to longer ventilator duration. Therefore, heredity likely affects both predisposition to ICU prognosis as well as the resource utilization.