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Tumor Necrosis Factor Gene Polymorphisms and the Variable Presentation and Outcome of Community-Acquired Pneumonia* FREE TO VIEW

Richard G. Wunderink, MD, FCCP; Grant W. Waterer, MBBS, FCCP; Rita M. Cantor, PhD; Michael W. Quasney, MD, PhD
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*From Methodist Le Bonheur Healthcare Foundation, University of Tennessee, Memphis, TN.

Correspondence to: Richard G. Wunderink, MD, FCCP, 501 Crews Wing, Methodist Healthcare, 1265 Union Ave, Memphis, TN 38104; e-mail: wunderir@methodisthealth.org

Chest. 2002;121(3_suppl):87S. doi:10.1378/chest.121.3_suppl.87S
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Tumor necrosis factor (TNF)-α is an integral part of the immune response to infection. A number of polymorphisms in or near the TNF-α gene are associated with variability in TNF-α production. The three polymorphisms with the best documented in vivo and in vitro effect on TNF-α production are the TNF-α-238, TNF-α-308, and lymphotoxin (LT)-α + 250 loci. At each locus, a G to A transition is associated with greater TNF-α production. We hypothesized that the A alleles of these three polymorphisms would be associated with greater mortality and a greater risk of septic shock in patients with community-acquired pneumonia (CAP).

A prospective cohort study of 272 patients with CAP was performed with genotype determined by polymerase chain reaction amplification and restriction enzyme digestion. Among these, 24 patients (8.8%) died and 28 patients (10.3%) had septic shock. Genotype distribution was as follows: TNF-α-238 AA, 0 (0%); GA, 27 (10.3%); GG, 244 (89.7%); TNF-α-308 AA, 19 (7.0%); GA, 64 (23.5%); GG, 189 (69.5%); LT-α + 250 AA, 82 (30.1%); GA, 133 (48.9%); and GG, 57 (21.0%). Linkage disequilibrium existed between the LT-α + 250 A allele and the TNF-α-308 G allele (p < 0.001), and the LT-α + 250 A allele and the TNF-α-238 A allele (p = 0.01). Only the GA genotype at the TNF-α-238 locus was associated with increased mortality (25% vs 6.5%, p = 0.004; relative risk, 3.7; 95% confidence interval, 1.7 to 8.2). In a logistic regression model, TNF-α-238 GA genotype remained an independent risk factor for death (p = 0.02) with an age-adjusted odds ratio of 3.6 (range, 1.27 to 11.34). In contrast to mortality, a strong association between LT-α + 250 AA genotype and the risk of septic shock was found (relative risk, 2.5; 95% confidence interval, 1.3 to 1.8), with nonsignificant trends to greater septic shock with carriage of A alleles at TNF-α-238 and TNF-α-308. Analysis of TNF-α-308: LT-α + 250 haplotypes found the risk of septic shock to be associated with the G-A haplotype (p = 0.01), but not the A-A haplotype. Carriage of the TNF-α-308: LT-α + 250 G-G haplotype was protective from septic shock (p = 0.01).

In conclusion, the A allele at the TNF-α-238 locus is associated with a significantly greater risk of death in patients with CAP. AA genotype at the LT-α + 250 locus is associated with a greater risk of septic shock, but this locus is most likely to be a marker of another, causative polymorphism.

Abbreviations: CAP = community-acquired pneumonia; LT = lymphotoxin; TNF = tumor necrosis factor




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