O07 - TNF-α, IL-6 and IL-8 cytokines in relation to TNF-α-308 G/A polymorphism in postoperative sepsis

Kavita Baghel, Rajeshwar Nath Srivastava, Abhijit Chandra, Jyotsna Agrawal, Hasan Raza Kazmi, Saloni Raj, King George's Medical University

Background: Early prediction of postoperative sepsis remains obscure. TNF-α also plays a major role in the clinical manifestations of sepsis, and serum levels inversely correlate with survival from severe sepsis. Inherited variability of cytokine production and genetic predisposition for fatal infectious diseases have been suggested. Several polymorphisms have been identified inside the TNF-α promoter, among which the G/A polymorphism at nucleotide position -308 was found directly affecting TNF-α expression. In sepsis, interest has particularly focused on the promoter TNF-308 G/A single nucleotide polymorphism.We investigated association of TNF-α-308 G/A polymorphism and serum level of cytokine TNF-α, IL-6 and IL-8 with the development of sepsis following major surgery.

Hypothesis: TNF-α-308 G/A polymorphism is associated with development of sepsis following surgery

Methods: 239 patients undergoing major elective gastrointestinal surgery were enrolled. Blood sample were drawn and genomic DNA was isolated. TNF-α-308 G/A polymorphism was studied using PCR-RFLP method. All patients were followed for 1 month following surgery for any evidence of sepsis. Serum cytokine TNF-α, IL-6 and IL-8 levels were measured pre and postoperatively by ELISA. Genotypes and cytokine levels were related to the occurrence of sepsis if any.

Results: 19.66%(n=47) patients developed postoperative sepsis. Overall mortality was 3.34%(n=8). The allele frequencies of G and A were 0.67 and 0.33 in patients with postoperative sepsis and 0.84 and 0.16 in patients without postoperative sepsis. Patients with postoperative sepsis were significantly (p=0.002) more likely to possess AA homozygous genotype with higher capacity to produce cytokine TNF-α (p<0.0001), IL-6 (p<0.0001) and IL-8 (p<0.0001) as compared to other genotypes. When compared with patients carrying at least one G allele (GG homozygous and GA heterozygous genotype), AA homozygous genotype was associated with an OR of 4.17 (p=0.003; 95% CI=1.5 to 11.48) for the development of sepsis. Compared with the homozygous GG genotype, the OR for the homozygous AA genotype was 5.18 (p=0.0008; 95% CI=1.82 to 14.76) for sepsis development.

Conclusions: TNF-α-308 G/A polymorphism is significantly associated with the development of postoperative sepsis with increased expression of cytokine TNF-α, IL-6 and IL-8.