Functional effect of polymorphisms in the promoter of TNFAIP3 (A20) in acute pancreatitis in the Han Chinese population.

Yugang Liu,Gang Dan,Ping Zeng,Ailin Wu,Guangyu Chen,Lijuan Wu,Wanqing Xu,David L Boone

doi:10.1371/journal.pone.0103104

Yugang Liu, Gang Dan + Show 6 more

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https://doi.org/10.1371/journal.pone.0103104

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Journal: PloS one	Publication Date: Jul 22, 2014
Citations: 9	License type: CC BY 4.0

Affiliation: Chengdu Military General Hospital

Abstract

BackgroundThe zinc finger protein A20 is an important negative regulator of inflammation; polymorphisms in the corresponding gene, TNFAIP3, have been reported to be associated with several inflammation diseases. However, only a few studies have focused on the relationship between TNFAIP3 polymorphisms and acute pancreatitis (AP).MethodsWe enrolled 201 healthy controls and 190 acute pancreatitis patients (including 47 systemic inflammatory response syndrome patients) for this study and used DNA sequencing to investigate polymorphisms in the TNFAIP3 promoter. The functional effects of these variants on transcriptional activity, A20 expression, NF-κB activity, and TNF-α and IL-1β levels, after in vitro lipopolysaccharide stimulation, were assessed.ResultsTwo SNPs (rs59693083 and rs5029924) in the TNFAIP3 promoter were selected based on bioinformatic analysis. Neither of these SNPs was associated with susceptibility to AP; however, acute pancreatitis patients who possessed the T allele of rs5029924 were more likely to experience systemic inflammatory response syndrome. Moreover, rs5029924 was found to affect TNFAIP3 promoter activity. After lipopolysaccharide stimulation, the expression of A20 protein significantly decreased, while the activity of NF-κB and the production of TNF-α and IL-1β significantly increased in whole blood leukocytes from subjects with the T allele.ConclusionThe rs5029924 polymorphism in the TNFAIP3 promoter may alter the risk of systemic inflammatory response syndrome in acute pancreatitis patients by influencing the expression of A20 protein.

Highlights

Acute pancreatitis (AP) is a syndrome of sudden-onset pancreatic inflammation characterized by upper abdominal pain, nausea, emesis, elevation of serum amylase and lipase levels, and changes noted upon abdominal imaging [1]
In about 20% of patients, the inflammatory process involves more than the pancreas, leading to a severe course; almost one-third of these patients progress to systemic inflammatory response syndrome (SIRS), and, subsequently, develop multi-organ dysfunction syndrome (MODS) [3,4], which is the main cause of death in critically ill patients
Subjects The protocols were approved by the Ethics Committee of Chengdu Military General Hospital, and informed written consent was obtained from all patients and controls before their enrollment in the study

Summary

Introduction

Acute pancreatitis (AP) is a syndrome of sudden-onset pancreatic inflammation characterized by upper abdominal pain, nausea, emesis, elevation of serum amylase and lipase levels, and changes noted upon abdominal imaging [1]. The inflammatory process in AP is usually limited to the pancreas or spreads only to regional tissues, so that the majority of patients experience mild disease. In about 20% of patients, the inflammatory process involves more than the pancreas, leading to a severe course; almost one-third of these patients progress to systemic inflammatory response syndrome (SIRS), and, subsequently, develop multi-organ dysfunction syndrome (MODS) [3,4], which is the main cause of death in critically ill patients. The specific mechanisms underlying the transition from local pancreatic inflammation to SIRS have not yet been elucidated clearly. Only a few studies have focused on the relationship between TNFAIP3 polymorphisms and acute pancreatitis (AP)

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Conclusion