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Critical Care

Open Access

TNFα promoter single nucleotide polymorphisms may influence gene expression in patients with severe sepsis

  • M Odwyer1,
  • M White1,
  • R McManus2 and
  • T Ryan1
Critical Care200711(Suppl 2):P448

Published: 22 March 2007


Severe SepsisCarrier StatusPromoter PolymorphismCaucasian PatientSensitive Data


We examined the association of TNFα promoter single nucleotide polymorphisms and haplotypes with gene expression in terms of mRNA levels and with outcome in a cohort of patients with severe sepsis.


Sixty-two Irish Caucasian patients presenting with severe sepsis were enrolled. Blood sampling was carried out on day 1 and on day 7. Mononuclear cells were isolated and TNFα mRNA quantified using the technique of quantitative real-time polymerase chain reaction (QRT-PCR). DNA was extracted and assayed for four TNFα promoter polymorphisms. Haplotypes were inferred using PHASE software.


Twenty-seven patients died. Patients carrying an A allele at position -863 produced more TNFα mRNA on day 1 than C homozygotes (P = 0.037). There was a trend for patients homozygous for the G allele at position -308 to produce more TNFα mRNA on day 1 than those carrying an A allele (P = 0.059). Carrier status for haplotype 1 (with A at position -863 and G at position -308) was associated with greater TNFα mRNA levels on day 1 (P = 0.0374). Carrier status for haplotype 4 (with C at position -863 and A at position -308) was associated with a nonsignificant decrease in TNFα mRNA levels on day 1 (P = 0.059). When directly compared, haplotype 1 was associated with significantly greater levels of TNFα mRNA than with haplotype 4 on day 1 (P = 0.02). Patients homozygous for the A allele at position -308 were more likely to succumb to severe sepsis than those carrying the G allele (P = 0.01).


These results contradict previous in vitro functional studies on the TNF2 allele. This may be secondary to the method of quantification of in vivo gene expression with QRT-PCR providing more accurate and sensitive data when compared with prior ELISA-based assays. Indeed, the extrapolation of functionality from in vitro functional genetic tests after lipopolysaccharide stimulation may be of questionable value. We conclude that genotypic analysis does have a place in risk stratification in sepsis and that genetic variants at positions -863 and -308, or sites in linkage disequilibrium with these variants, may influence TNFα production.

Authors’ Affiliations

St James's Hospital, Dublin, Ireland
Trinity College, Dublin, Ireland


© BioMed Central Ltd. 2007