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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{at}methodisthealth.org
Tumor necrosis factor (TNF)-
is an integral part of the immune
response to infection. A number of polymorphisms in or near the TNF-
gene are associated with variability in TNF- production. The three
polymorphisms with the best documented in vivo and in
vitro effect on TNF- production are the TNF--238,
TNF--308, and lymphotoxin (LT)- + 250 loci. At each locus, a G
to A transition is associated with greater TNF- 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--238 AA, 0 (0%); GA, 27 (10.3%); GG, 244
(89.7%); TNF--308 AA, 19 (7.0%); GA, 64 (23.5%); GG,
189 (69.5%); LT- + 250 AA, 82 (30.1%); GA, 133
(48.9%); and GG, 57 (21.0%). Linkage disequilibrium existed between
the LT- + 250 A allele and the TNF--308 G allele
(p < 0.001), and the LT- + 250 A allele and the TNF--238 A
allele (p = 0.01). Only the GA genotype at the TNF--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--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- + 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--238 and TNF--308. Analysis of
TNF--308: LT- + 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--308: LT- + 250 G-G haplotype
was protective from septic shock (p = 0.01).
In conclusion, the A allele at the TNF--238 locus is associated with
a significantly greater risk of death in patients with CAP. AA genotype
at the LT- + 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.
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