HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease. (April 2018)

• Record Type: Journal Article
• Authors: Huang, Ying-Hsien; Kuo, Hsing-Chun; Li, Sung-Chou; Cai, Xin-Yuan; Liu, Shih-Feng; Kuo, Ho-Chang
• Is Part Of: Journal of molecular and cellular cardiology. Volume 117(2018)
• Page Start: 82
• Page End: 87
• Publication Date: 2018-04
• Subjects: Hepcidin -- HAMP -- Kawasaki disease -- Methylation; CAL coronary artery lesions -- CAA coronary artery aneurysm -- ELISA enzyme-linked immunoassay -- IVIG intravenous immunoglobulin -- KD Kawasaki disease -- PCR Polymerase chain reaction -- SVM Support vector machines; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2018.02.017
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Kawasaki disease (KD) is the most common coronary vasculitis to appear in children with anemia and has been associated with elevated plasma hepcidin levels. We recruited a total of 241 cases, including 18 KD patients, who were tested both prior to receiving intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, and 18 febrile controls, who were observed in the Illumina HumanMethylation450 BeadChip study for their CpG markers. The remaining cases consisted of another 92 KD patients and 113 controls that were used for validation by pyrosequencing. We performed a genetic functional study using Luciferase assays. A support vector machine (SVM) classification model was adopted to identify KD patients and control subjects. In this study, KD patients clearly demonstrated a significantly epigenetic hypomethylation of HAMP promoter compared to controls. After receiving IVIG treatment, the hypomethylation status in KD patients was restored, and we observed a significant opposite tendency between the DNA methylation of target CpG sites (cg23677000 and cg04085447) and the hepcidin level. Furthermore, reporter gene assays were used to detect target CpG sites, the methylation of which displayed decreased levels of HAMP gene expression. Of particular note, we developed a SVM classification model with a 90.9% sensitivity, a 91.9% specificity, and 0.94 auROC in the training set. An independent blind cohort also had good performance (96.1% sensitivity and 89.7% specificity). In this study, we demonstrate HAMP promoter hypomethylation, which upregulates hepcidin expression in KD patients. Furthermore, the reliability and robustness of our SVM classification model can accurately serve as KD biomarkers. Highlights: Kawasaki disease patients demonstrate epigenetic hypomethylation of HAMP promoter. HAMP promoter hypomethylation can upregulate of hepcidin expression. Methylation of HAMP and hepcidin levels may be biomarkers for Kawasaki disease.