Tumor necrosis factor-α: investigation of gene polymorphism and regulation of TACE-TNF-α system in patients with acute myocardial infarction

A polymorphism within tumor necrosis factor-alpha (TNF-alpha) gene promoter and contribution of TNF-alpha converting enzyme (TACE) have been reported to be associated with TNF-alpha production which may increase susceptibility to heart failure such as acute myocardial infarction (AMI). However, the relationship between this polymorphism and susceptibility to AMI and the mechanism of TACE-TNF-alpha system regulation has poorly been studied. Genomic DNA and peripheral blood mononuclear cells (PBMCs) of patients with AMI and control subjects was extracted. The -308 G/A TNF-alpha polymorphism was detected. The mRNA transcription and protein expression levels of TNF-alpha and TACE were analyzed by real time RT-PCR and flow cytometry respectively as well as plasma TNF-alpha by ELISA. The 'A' allele frequency of TNF-alpha was significantly more frequent in the patients than controls (P < 0.001). There were statistically significant differences in TNF-alpha and TACE mRNA and protein levels as well as circulating TNF-alpha in the patients. However, these levels were higher in the patients who carry 'A' allele. There were significant positive correlation between these mRNAs and protein expression levels (r = 0.66, P < 0.001, r = 0.78, P < 0.001 respectively). These data suggest that genetic polymorphism in TNF-alpha might be helpful for determining susceptibility to AMI in Iranian patients. The TACE-TNF-alpha system in circulating leucocytes is stimulated which these results demonstrate that in patients with AMI, TACE expression in PBMC increases with TNF-alpha expression and processing of TNF-alpha in PBMC might be regulated by TACE at transcriptional, translational, and post-translational levels in AMI.