TNF-alpha gene (TNFA) variants increase risk for multi-organ dysfunction syndrome (MODS) in acute pancreatitis.

Abstract

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.

• Authors: Faraz Bishehsari, Arun Sharma, Kimberly Stello, Chad Toth, Michael Richard O'Connell, Anna C Evans, Jessica LaRusch, Venkata Muddana, Georgios I Papachristou, David C Whitcomb
• Journal: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] (Pancreatology) 2012 Mar-Apr Vol. 12 Issue 2 Pg. 113-8 ISSN: 1424-3911 [Electronic] Switzerland
• PMID: 22487520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 IAP and EPC. All rights reserved.

Chemical References

• Tumor Necrosis Factor-alpha

Topics

• Acute Disease
• Comorbidity
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genotype
• Humans
• Male
• Middle Aged
• Multiple Organ Failure (epidemiology, genetics)
• Pancreatitis (epidemiology, genetics)
• Pennsylvania (epidemiology)
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Prospective Studies
• Risk Factors
• Tumor Necrosis Factor-alpha (genetics)