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Abstract
Kawasaki disease (KD) is a type of acute febrile vasculitis syndrome and is the most frequent cause of cardiac illness in children under the age of five years old. Although the etiology of KD remains largely unknown, some recent genome-wide studies have indicated that epigenetic factors may be important in its pathogenesis.We enrolled 24 KD patients and 24 non-KD controls in this study to access their DNA methylation status using HumanMethylation450 BeadChips. Another 34 KD patients and 62 control subjects were enrolled for expression validation. Of the 3193 CpG methylation regions with a methylation difference ≥ 20% between KD and controls, 3096 CpG loci revealed hypomehtylation, with only 3% being hypermethylated. Pathway buildup identified 11 networked genes among the hypermethylated regions, including four transcription factors: nuclear factor of activated T-cells 1, v-ets avian erythroblastosis virus E26 oncogene homolog 1, runt related transcription factor 3, and retinoic acid receptor gamma, as well as the activator β-catenin. Ten of these network-selected genes demonstrated a significant decrease in mRNA in KD patients, whereas only CTNNB1 significantly decreased in correlation with coronary artery lesions in KD patients. Furthermore, CTNNB1-silenced THP-1 monocytic cells drastically increased the expression of CD40 and significantly increased the expression of both CD40 and CD40L in cocultured human coronary artery endothelial cells.This study is the first to identify network-based susceptible genes of hypermethylated CpG loci, their expression levels, and the functional impact of β-catenin, which may be involved in both the cause and the development of KD.
Highlights
A form of acute febrile systemic vasculitis, Kawasaki disease (KD) was first described by Kawasaki et al in 1974 [1]; its origins are still generally unknown today
1,703 genes were found distributed among 3,193 CpG regions (DMRs) with a methylation difference ≥ 20% between KD patients and normal control subjects (NC)
To improve the understanding of the biological context of the changes in the corresponding genes of DMRs in KD, 39 genes imposed on 97 hypermethylated loci and 1,664 genes imposed on 2,096 hypomethylated loci were analyzed using Ariadne’s pathway buildup for direct interaction and were further enriched using sub-network analysis (SNEA) to identify the respective putative networks
Summary
A form of acute febrile systemic vasculitis, Kawasaki disease (KD) was first described by Kawasaki et al in 1974 [1]; its origins are still generally unknown today. This disease affects children around the world, those under the age of five years old. Previous genome-wide association studies (GWAS) have shown that many genes are associated with susceptibility to KD, including FCGR2A [6], CD40 [7], BLK [8], and ITPKC [9]. The purpose of this study is to examine more detailed epigenetic changes in the susceptibility and pathogenesis of KD using HumanMethylation450 BeadChip, as well as to investigate potential mechanisms using a cell-cell interacting vasculitis model
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