1. ¹Institute of Cell and Molecular Science & William Harvey Research Institute, Barts and The London Queen Mary's School of Medicine and Dentistry, University of London, London, UK
2. ²Clinical Genomics Group, National Heart and Lung Institute, Imperial College, London, UK
3. ³Kolling Institute of Medical Research and Royal North Shore Hospital, University of Sydney, St Leonard's, NSW, Australia
4. ⁴Intensive Care Unit, John Radcliffe Hospital, Oxford, UK

Correspondence: Professor CJ Hinds, Department of Anaesthesia and Intensive Care Medicine, Barts and The London Queen Mary's School of Medicine and Dentistry, London EC1A 7BE, UK. E-mail: c.j.hinds@qmul.ac.uk

Received 6 July 2004; Revised 13 August 2004; Accepted 16 August 2004; Published online 4 November 2004.

Abstract

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P=0.02), sTNFRSF1A (P=0.005) and sTNFRSF1B (P=0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R=0.51, P<0.001; sTNFRSF1B R=0.53, P<0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.