Differential Methylation Signatures in Severely Calcified Carotid Plaques by Genome-Wide Comprehensive Analysis

Author(s): Hiroyuki Katano*, Yusuke Nishikawa, Hiroshi Yamada, Tomoyasu Yamanaka, Mitsuhito Mase

Journal Name: Current Neurovascular Research

Volume 17 , Issue 5 , 2020

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Graphical Abstract:


Background: The precise cellular behaviors of calcification, including its molecular and genetic activities, have not yet been fully established for carotid plaques.

Objective: We sought specific genes with tissue-specific differential methylation associated with carotid calcification status.

Methods: We classified eight plaques from carotid endarterectomy patients as high- or low-calcified based on their Agatston calcium scores. We analyzed differential DNA methylation and performed bioinformatics data mining.

Results: A high correlation of average methylation levels (β-values) in promoter regions between high- and low-calcified plaque groups was observed. A principal component analysis of DNA methylation values in promoters of specimens revealed two independent clusters for high- and lowcalcified plaques. Volcano plots for methylation differences in promoter regions showed that significantly hypomethylated probes were more frequently found for high-calcified plaques than more methylated probes. Differential hypomethylation of receptor activity-modifying protein 1 (RAMP1) in high-calcified plaques was commonly extracted in both the promoter region and the cytosinephosphate- guanine (CpG) island shore region, where differential methylation had been reported to be more tissue-specific. Kyoto Encyclopedia of Genes and Genomes pathway analysis annotated a pathway associated with vascular smooth muscle contraction in the differentially methylated genes of the promoter and CpG island shore regions in high-calcified plaques.

Conclusion: Among the extracted differentially methylated genes, hypomethylated genes were more dominant than more methylated genes. The augmentation of RAMP1 by hypomethylation may contribute to the enhancement of anti-atherosclerotic effects and hence stability in high-calcified plaques. These results contribute to our understanding of the genetic signatures associated with calcification status and cellular activity in carotid plaques.

Keywords: Carotid plaque, calcification, carotid endarterectomy, DNA, methylation, genome, epigenetics.

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Article Details

Year: 2020
Published on: 29 October, 2020
Page: [534 - 628]
Pages: 95
DOI: 10.2174/1567202617666201029145028
Price: $65

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