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

Introduction

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.

Methods

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.

Results

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).

Conclusion

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.

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Odwyer, M., White, M., McManus, R. et al. TNFα promoter single nucleotide polymorphisms may influence gene expression in patients with severe sepsis. Crit Care 11, P448 (2007). https://doi.org/10.1186/cc5608

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Keywords

  • Severe Sepsis
  • Carrier Status
  • Promoter Polymorphism
  • Caucasian Patient
  • Sensitive Data