The human blood DNA methylome identifies crucial role of β-catenin in the pathogenesis of Kawasaki disease

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.

Decreased DNA methyltransferases expression is associated with coronary artery lesion formation in Kawasaki disease

“…More recently, genome-wide epigenomic studies have been performed for several vasculitides 25. Our results of a decreased expression of DMNT1 and an increased expression of TET2 are consistent with our previous reports of hypomethylation of promotor of β-catenin 16, NOD-like receptors 13, matrix metalloproteinases 9, toll-like receptors 9 and HAMP 11 in KD patients when compared to age-matched controls that presented with fever/without fever and no history of KD. Global genomic hypomethylation in PBMCs has been observed not only in our recent studies of Kawasaki disease, but also in a number of inflammatory and autoimmune diseases, such as systemic lupus erythematous (SLE), rheumatoid arthritis (RA), etc., where it also correlates with aberrant gene expression that likely contributes to pathogenesis 27-30.…”

“…The global DNA hypomethylation in the PBMCs of KD patients was primarily observed in our previous study using HumanMethylation27 BeadChip assay, in which we identified an increase of FCGR2A associated with its hypomethylation and a susceptibility to IVIG resistance 33. We further illustrated a more comprehensive study using HumanMethylation27 BeadChip assay, which showed that 97% of CpG regions with a methylation difference ≥ 20% between KD and controls were hypomethylated 16. We determined that a significant decrease of β-catenin was associated with its hypomethylation in the promoter, as well as in the pathogenesis and cause of coronary arterial lesions in KD.…”

“…Chen et al reported that, of the 3193 CpG methylation regions with a methylation difference ≥ 20% between KD and controls, 3096 CpG loci revealed hypomethylation (97%) and only 3% hypermethylation 16, which indicates that more than 97% of genes in KD patients have a hypomethylation status, as well as a potential increase in gene expression levels. KD is a specific disease with an activated status of most genes, most of which have the condition of overexpression, including T helper 1 (Th1), Th2, Th17, innate immunity, adaptive immunity, inflammatory cytokines, chemokines, etc.…”

Kawasaki Disease: Global Burden and Genetic Background

“…In 2018 Chen et al [55] compared the CpG methylation status in KD patients and controls, and found that most of CpG loci (97%) revealed hypomethylation with only 3% showed hypermethylation; a finding suggesting that the majority of genes in KD patients have a hypomethylation status which results in an over-expression of these genes with increased activity of varies immune mechanisms including T helper 1 (Th1), Th2, Th17, innate immunity, acquired immunity, cytokines, etc. The exact reason why most genes are activated remains uncertain.…”

The rs6505162 C>A polymorphism in themiRNA-423gene exhibits a protective element of coronary artery in a southern Chinese population with Kawasaki disease

“…(16) Several genes in the hypermethylated region were studied by Chen, and the correlation between the hypermethylated CpG locus and the pathogenesis of KD was mentioned for the first time. (17) These are some of the mechanisms of KD above.…”