Identification of an association between genomic hypomethylation of fcgr2a and susceptibility to Kawasaki disease and intravenous immunoglobulin resistance by DNA methylation array

Objective Kawasaki disease (KD) is characterized by systemic vasculitis, and it is the most common acquired heart disease in children. However, the etiology and immunopathogenesis of KD are still unclear. A genome-wide association study (GWAS) identified polymorphisms in CD40, BLK, and FCGR2A as the susceptibility genes for KD. No epigenetic array studies of KD have previously been published. This study was undertaken to investigate differences in DNA methylation in patients with KD as compared to controls. Methods The HumanMethylation27 BeadChip (Illumina) was used to survey the differences in DNA methylation between KD patients and controls. DNA methylation array validation was performed in a separate cohort by pyrosequencing assay and reporter gene assays. Messenger RNA (mRNA) expression was determined, and the association of methylation with response to intravenous immunoglobulin (IVIG) treatment was analyzed. Results HumanMethylation27 BeadChip assay showed a 15% difference in methylation of 10 genes between KD patients and controls. The FCGR2A cg24422489 group, which was recently reported to be associated with KD susceptibility in a GWAS, had significant hypomethylation of 15.54% less in the KD group than in the control group. Validation of FCGR2A methylation in another cohort also showed significant hypomethylation in the KD group (5 of 5 CpG sites [P < 0.01]; n = 43 in the KD group and n = 55 in the control group). KD patients with IVIG resistance showed hypomethylation of 5 CpG sites (P < 0.05). FCGR2A mRNA expression was significantly increased in patients in the acute stage of KD compared to controls. Reporter gene assays indicated that the CpG sites of the FCGR2A promoter region were sufficient to modulate gene expression. Conclusion This is the first study to examine the DNA methylation array in KD and identify a role of hypomethylation of FCGR2A in susceptibility to KD and IVIG resistance.