부산대학교 도서관

Tumour necrosis factor-alpha (TNFα) has been implicated in the pathogenicity of severe sepsis by both genetic association studies and animal models. Conflicting functional data have emerged in relation to genetic variants and TNFα protein production. Therefore, we assessed the functionality of TNFα genetic variants in terms of mRNA production and their potential influence on outcome in the setting of severe sepsis. Sixty-two Irish Caucasian patients presenting with severe sepsis were recruited and TNFα mRNA and protein levels were quantified. Patient DNA was analysed for the presence of common promoter polymorphisms and haplotypes were inferred. An A allele at position –863 was associated with more TNFα mRNA on day 1 compared to C homozygotes ( P = 0.037). There was a trend for G homozygotes at position –308 to produce more TNFα mRNA on day 1 than those carrying an A allele ( P = 0.059). The presence of an A allele at –863 was associated with greater levels of TNFα mRNA in comparison with patients carrying the A allele at –308 on day 1 ( P = 0.02). Patients homozygous for the A allele at position –308 had a higher mortality than those carrying the G allele ( P = 0.01). Our data are consistent with recent reports suggesting that a deficient proinflammatory response may be harmful in human sepsis. This deficient inflammatory response may be mediated in part by polymorphisms in the TNFα promoter. [ABSTRACT FROM AUTHOR]