BACKGROUND: Acute severe pancreatitis (ASP) has an unpredictable course and outcome. Polymorphisms of the tumor necrosis factor (TNF) gene have been related to TNF production and outcome in a variety of inflammatory diseases. We assessed whether TNF gene polymorphism and plasma concentrations of TNF-alpha were related to the occurrence of ASP and septic shock from it. METHODS: The study included 208 patients (102 with ASP, 106 with acute mild pancreatitis) and 116 healthy volunteers. TNF-beta and TNF-alpha-308 polymorphisms were performed by analyzing NcoI-digested DNA fragment obtained by polymerase chain reaction (PCR). HLA-DRB1*0301 (HLA-DR3) typing was performed by sequence-specific oligonucleotide typing on PCR-amplified genomic DNA. Plasma concentrations of TNF-alpha were measured by solid-phase enzyme-amplified sensitivity immunoassay. RESULTS: The overall TNF2 allele frequency and TNFB2 allele frequency were similar in patients with mild or severe pancreatitis. Further, no significant difference in gene polymorphism frequencies was noted between patients with acute pancreatitis and controls. TNF2 frequency was significantly increased in septic shock patients compared with nonseptic shock patients (53.8 vs 22.4%; P = 0.003), as was TNFB2 frequency (88.5 vs 63.2%; P = 0.015). A linkage disequilibrium between TNF2 allele and HLA-DR3 was seen, this haplotype was not associated with severity of acute pancreatitis or outcome of septic shock in ASP patients. With regard to the mortality rate in patients who developed septic shock, those with a TNF2 allele had a significantly higher rate of mortality than those with a TNF1 allele (expired: 8 vs 1, P = 0.018). Plasma levels of TNF-alpha did not differ significantly in ASP patients displaying different alleles of the TNF gene studied. CONCLUSIONS: Results indicate that the TNF gene polymorphisms studied play no part in determination of disease severity or ASP susceptibility; however, they are both strongly related to the development of septic shock in ASP. TNF2 allele was associated with death as a result of ASP-associated septic shock.
BACKGROUND: Acute severe pancreatitis (ASP) has an unpredictable course and outcome. Polymorphisms of the tumor necrosis factor (TNF) gene have been related to TNF production and outcome in a variety of inflammatory diseases. We assessed whether TNF gene polymorphism and plasma concentrations of TNF-alpha were related to the occurrence of ASP and septic shock from it. METHODS: The study included 208 patients (102 with ASP, 106 with acute mild pancreatitis) and 116 healthy volunteers. TNF-beta and TNF-alpha-308 polymorphisms were performed by analyzing NcoI-digested DNA fragment obtained by polymerase chain reaction (PCR). HLA-DRB1*0301 (HLA-DR3) typing was performed by sequence-specific oligonucleotide typing on PCR-amplified genomic DNA. Plasma concentrations of TNF-alpha were measured by solid-phase enzyme-amplified sensitivity immunoassay. RESULTS: The overall TNF2 allele frequency and TNFB2 allele frequency were similar in patients with mild or severe pancreatitis. Further, no significant difference in gene polymorphism frequencies was noted between patients with acute pancreatitis and controls. TNF2 frequency was significantly increased in septic shockpatients compared with nonseptic shock patients (53.8 vs 22.4%; P = 0.003), as was TNFB2 frequency (88.5 vs 63.2%; P = 0.015). A linkage disequilibrium between TNF2 allele and HLA-DR3 was seen, this haplotype was not associated with severity of acute pancreatitis or outcome of septic shock in ASPpatients. With regard to the mortality rate in patients who developed septic shock, those with a TNF2 allele had a significantly higher rate of mortality than those with a TNF1 allele (expired: 8 vs 1, P = 0.018). Plasma levels of TNF-alpha did not differ significantly in ASPpatients displaying different alleles of the TNF gene studied. CONCLUSIONS: Results indicate that the TNF gene polymorphisms studied play no part in determination of disease severity or ASP susceptibility; however, they are both strongly related to the development of septic shock in ASP. TNF2 allele was associated with death as a result of ASP-associated septic shock.
Authors: B D Freeman; C R Kennedy; H L Frankel; B Clarridge; D Bolcic-Jankovic; E Iverson; E Shehane; A Celious; B A Zehnbauer; T G Buchman Journal: Pharmacogenomics J Date: 2009-12-08 Impact factor: 3.550