title: Genetic polymorphisms within tumor necrosis factor gene promoter region: a role for susceptibility to ventilator-associated pneumonia.
abstract: Debatable findings exist among various studies regarding the impact of single nucleotide polymorphisms (SNPs) within the promoter region of the tumor necrosis factor (TNF) gene for susceptibility to infections. Their impact was investigated in a cohort of mechanically ventilated patients who developed ventilator-associated pneumonia (VAP). Two-hundred and thirteen mechanically ventilated patients who developed VAP were enrolled. Genomic DNA was extracted and SNPs at the -376, -308 and -238 position of the promoter region of the TNF gene were assessed by restriction fragment length polymorphisms. Monocytes were isolated from 47 patients when they developed sepsis and stimulated by bacterial endotoxin for the production of TNFα and of interleukin-6 (IL-6). Patients were divided into two groups; 166 patients bearing only wild-type alleles of all three studied polymorphisms; and 47 patients carrying at least one A allele of the three studied SNPs. Time between start of mechanical ventilation and advent of VAP was significantly shorter in the second group than in the first group (log-rank: 4.416, p: 0.041). When VAP supervened, disease severity did not differ between groups. Stimulation of TNFα and of IL-6 was much greater by monocytes for patients carrying A alleles. Carriage of at least one A allele of the three studied SNPs at the promoter region of the TNF-gene is associated with shorter time to development of VAP but it is not associated with disease severity. Findings may be related with a role of the studied SNPs in the production of pro-inflammatory cytokines.
authors.affiliation: Fourth Department of Internal Medicine, University of Athens, Medical School, Greece.
authors.forename: Antigoni
authors.initials: A
authors.lastname: Kotsaki
authors.forename: Maria
authors.initials: M
authors.lastname: Raftogiannis
authors.forename: Christina
authors.initials: C
authors.lastname: Routsi
authors.forename: Fotini
authors.initials: F
authors.lastname: Baziaka
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kotanidou
authors.forename: Anastasia
authors.initials: A
authors.lastname: Antonopoulou
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Orfanos
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Katsenos
authors.forename: Pantelis
authors.initials: P
authors.lastname: Koutoukas
authors.forename: Diamantis
authors.initials: D
authors.lastname: Plachouras
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Mandragos
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D053717:Pneumonia, Ventilator-Associated / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012121:Respiration, Artificial; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha