Functional Effect of Polymorphisms in the Promoter of TNFAIP3

The 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). We 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-[kappa]B activity, and TNF-[alpha] and IL-1[beta] levels, after in vitro lipopolysaccharide stimulation, were assessed. Two 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-[kappa]B and the production of TNF-[alpha] and IL-1[beta] significantly increased in whole blood leukocytes from subjects with the T allele. The 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.