Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) single nucleotide polymorphisms: Importance in ARDS in septic pediatric critically ill patients

Accumulating evidence indicates that genetic background influences the outcome of sepsis, which despite medical advances continues to be a major cause of morbidity and mortality. This study aimed to evaluate the influence of SNPs LTA +252A > G, TNF-863C > A and TNF-308G > A on susceptibility to sepsis, acute respiratory distress syndrome (ARDS), septic shock and sepsis mortality. A prospective case-control study was carried out in a Brazilian pediatric intensive care unit and included 490 septic pediatric patients submitted to mechanical ventilation and 610 healthy children. No SNP association was found with respect to sepsis susceptibility. Nevertheless, a haplotype was identified that was protective against sepsis (+252A/−863A/−308G; OR = 0.65; p = 0.03). We further observed protection against ARDS in TNF-308 GA genotype carriers (OR = 0.29; p = 0.0006) and −308A allele carriers (OR = 0.40; p = 0.003). In addition, increased risk for ARDS was detectable with the TNF-863 CA genotype (OR = 1.83; p = 0.01) and the −863A carrier status (OR = 1.82; p = 0.01). After stratification according to age, this outcome remained significantly associated with the −308GA genotype in infants. Finally, protection against sepsis-associated mortality was found for the TNF-308 GA genotype (OR = 0.22; p = 0.04). Overall, our findings document a protective effect of the TNF-308 GA genotype for the ARDS and sepsis mortality outcomes, further providing evidence for an increased risk of ARDS associated with the TNF-863 CA genotype. Trial registration (www.clinicaltrials.gov): NCT00792883.