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TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis
Faraz Bishehsari1, Arun Sharma, Kimberly Stello
1Department of Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Background/Objectives:
Acute pancreatitis (AP) is a complex inflammatory syndrome with unpredictable progression to systemic inflammation and multi-organ dysfunction syndrome (MODS). Tumor necrosis factor alpha (TNF-α) is a cytokine that may link inflammation to the systemic inflammatory response syndrome (SIRS), which usually precedes MODS. Small genetic cohort studies of the TNFA promoter in AP produced ambiguous results. We performed a comprehensive evaluation of TNFA promoter variants to assess both susceptibility to AP and risk of progression to MODS.
Methods:
We prospectively ascertained 401 controls and 211 patients with AP that were assessed for persistent SIRS (>48 h) and MODS. MODS was defined as failure of ≥2 organ systems (cardiovascular, pulmonary, and/or renal) persisting more than 48 h. Subjects were genotyped by DNA sequencing and analyzed for SNPs at -1031 C/T (rs1799964), -863 A/C (rs1800630), -857 C/T (rs1799724), -308 A/G (rs1800629), and -238 A/G (rs361525).
Results:
Twenty-three of 211 AP patients (11%) developed MODS. TNFA promoter variants were not associated with susceptibility to AP, but progression to MODS was associated with the minor allele at -1031C (56.5% vs. 32.4% P = 0.022, OR: 2.7; 95%CI: 1.12-6.51) and -863A (43.5% vs. 21.8% P = 0.022, OR: 2.76; 95%CI: 1.12-6.74).
Conclusion:
TNFA promoter variants do not alter susceptibility to AP, but rather the TNF-α expression-enhancing -1031C and -863A alleles significantly increased the risk of AP progression to MODS. These data, within the context of previous studies, clarify the risk of specific genetic variants in TNFA and therefore the role of TNF-α in the overall AP syndrome.
Insights
Genetic variants in the Tumor Necrosis Factor Alpha (TNF-α) promoter influence acute pancreatitis (AP) progression to multi-organ dysfunction syndrome (MODS). Specific alleles increase the risk of developing MODS, but not AP susceptibility.
Area of Science:
- Genetics
- Immunology
- Gastroenterology
Background:
- Acute pancreatitis (AP) is a severe inflammatory condition with unpredictable progression.
- Tumor necrosis factor alpha (TNF-α) plays a role in systemic inflammation and multi-organ dysfunction syndrome (MODS) development.
- Previous studies on TNFA promoter variants in AP have yielded inconclusive results.
Purpose of the Study:
- To comprehensively evaluate TNFA promoter variants for their association with AP susceptibility.
- To assess the risk of AP progression to MODS based on TNFA promoter genotypes.
- To clarify the role of TNF-α in AP pathogenesis through genetic analysis.
Main Methods:
- Prospective study of 211 AP patients and 401 controls.
- Assessment of persistent systemic inflammatory response syndrome (SIRS) and MODS.
- Genotyping of TNFA promoter single nucleotide polymorphisms (SNPs) including -1031 C/T, -863 A/C, -857 C/T, -308 A/G, and -238 A/G using DNA sequencing.
Main Results:
- AP patients with MODS showed an 11% incidence.
- No association was found between TNFA promoter variants and susceptibility to AP.
- The minor alleles at -1031C and -863A in the TNFA promoter were significantly associated with an increased risk of progression to MODS (OR: 2.7 and 2.76, respectively).
Conclusions:
- TNFA promoter variants do not influence susceptibility to acute pancreatitis.
- Specific TNF-α expression-enhancing alleles (-1031C and -863A) are linked to a higher risk of AP progression to MODS.
- These findings elucidate the specific genetic risks associated with TNFA variants in AP and the role of TNF-α in its progression.
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