title: Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) single nucleotide polymorphisms: importance in ARDS in septic pediatric critically ill patients.
abstract: 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.
authors.affiliation: Paediatric Intensive Care Unit, Dept. Paediatrics, Instituto Fernandes Figueira, FIOCRUZ, Brazil. zina@iff.fiocruz.br
authors.forename: Z M
authors.initials: ZM
authors.lastname: Azevedo
authors.forename: D B
authors.initials: DB
authors.lastname: Moore
authors.forename: F C
authors.initials: FC
authors.lastname: Lima
authors.forename: C C
authors.initials: CC
authors.lastname: Cardoso
authors.forename: R
authors.initials: R
authors.lastname: Bougleux
authors.forename: G I
authors.initials: GI
authors.lastname: Matos
authors.forename: R A
authors.initials: RA
authors.lastname: Luz
authors.forename: P
authors.initials: P
authors.lastname: Xavier-Elsas
authors.forename: E P
authors.initials: EP
authors.lastname: Sampaio
authors.forename: M I
authors.initials: MI
authors.lastname: Gaspar-Elsas
authors.forename: M O
authors.initials: MO
authors.lastname: Moraes
mesh_terms: D000293:Adolescent; D000483:Alleles; D001938:Brazil; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D015278:Intensive Care Units, Pediatric; D008233:Lymphotoxin-alpha / Q000235:genetics* / Q000276:immunology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D012306:Risk; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
chemical_list: D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha