Tumor necrosis factor-β Nco1 polymorphism and susceptibility to sepsis following major elective surgery

Abstract

Background: Post-operative sepsis remains a substantial cause of morbidity and mortality. In injured patients, that a polymorphism of the gene for tumor necrosis factor-β (TNF-β) has been related to the development of sepsis. Genetic factors may also have a role in etio-pathogenesis of sepsis following surgery. We investigated the relationship of the polymorphism of the gene for TNF-β and the serum concentration of TNF-α to the development of sepsis after elective major surgery.

Methods: The study population consisted of 211 patients undergoing major elective surgery. The NcoI polymorphism of TNF-β was studied in genomic DNA through the analysis of restriction fragments of Nco1-digested DNA with the polymerase chain reaction (PCR). All patients were followed for 1 mo after surgery for any evidence of sepsis. Serum concentrations of TNF-α were measured pre- and post-operatively by enzyme linked immunosorbent assay (ELISA). Genotypes of TNF-β and the production of TNF-α were related to the occurrence of sepsis.

Results: Post-operative sepsis developed in 21.8% (n=46) of the patients. The overall mortality was 4.2% (n=9). The overall allele frequency of the TNF-β genotype was 0.32 for TNFB1 and 0.68 for TNFB2. Within the TNF-β genotype, 11.84% (n=25) of the patients were homozygous recessive for TNFB1, 41.23% (n=87) were heterozygous, with TNFB1/TNFB2, and 46.91% (n=99) were homozygous dominant for TNFB2. The incidence of post-operative sepsis was significantly (p=0.01) higher in patients homozygous for the TNFB2 allele. When compared with patients carrying at least one TNFB1 allele (TNFB1 homozygous and heterozygous genotype), the TNFB2 homozygous genotype was associated with an odds ratio (OR) of 2.60 (p=0.005; 95% CI 1.32-5.15) for the development of sepsis. As compared with that for the heterozygous genotype, the OR for the homozygous TNFB2 genotype was 3.00 (p=0.003; 95% CI 1.39-6.44). In patients with post-operative sepsis, serum concentrations of TNF-α were significantly higher (p=0.02) in TNFB2 homozygous individuals than in those of individuals of the other TNF-β genotypes.

Conclusion: The development of sepsis was associated with a greater capacity to produce TNF-α after surgery. The Nco1 polymorphism of the TNF-β gene was associated with the development of post-operative sepsis with an increased serum concentration of TNF-α. In patients without post-operative sepsis, polymorphism of the TNF-β gene was not related to different levels of TNF-α production. This indicates an association between polymorphism of the TNF-β gene and post-operative sepsis, suggesting the TNFB2/B2 genotype as a high-risk factor for the development of sepsis after elective surgery.