gms | German Medical Science

Introduction: Up-regulation of inflammatory responses is considered a driving force of atherosclerotic lesion development. Nuclear factor (NF)-kB plays a major role in regulating these inflammatory processes. Multiple mechanisms normally ensure proper termination of NF-kB activation. In this context, the intracellular ubiquitin-editing protein A20 is a key player in the negative feedback regulation of NF-kB signalling in response to multiple stimuli. The possibility that A20 and reduction in NF-kB activity might modulate risk of atherosclerosis was suggested by findings of linkage between the A20 gene region and atherosclerosis in an intercross between atherosclerosis-susceptible and –resistant mice.

The aim of our study was to determine whether genetic variability at the A20 locus modulates TNFa expression in the atherosclerotic plaque.

Materials and methods: Atherosclerotic lesions from 172 patients have been collected intraoperativly (71 patients with severe stenosis of the internal carotid artery; 63 patients with peripheral artery disease; 38 patients with aortic aneurysm). DNA and RNA were isolated from the plaque. TNFa mRNA-expression was determined by quantitative RT-PCR. Genotyping of known single nucleotide polymorphisms (SNPs) in the A20 gene was performed.

Results: A non-coding SNP (rs610604) in the A20 gene had significant influence on TNFa expression. Wildtype patients (230.9 ± 28.2; p<.05) showed significant lower TNFa expression in the atherosclerotic plaque than heterozygotes (296.1 ± 43.8) and minor allele homozygotes (658.4 ± 224.2).

Conclusion: We identified a non-coding SNP (rs610604) in the exon of the A20 gene that causes increased TNFa expression. We suppose this is mediated by allelic differences in A20 expression. If A20 polymorphisms influence the atherosclerosis risk in the general population needs to be determined by future studies.