Correlation of<i>HAMP</i>gene polymorphisms and expression with the susceptibility and length of hospital stays in Taiwanese children with Kawasaki disease

Huang, Ying; Yang, Kuender D.; Hsu, Yu Wen; Lu, Hsing Fang; Wong, Henry Sung Ching; Yu, Hong‐Ren; Kuo, Hsing Chun; Huang, Fu Chen; Lo, Mao Hung; Hsieh, Kai‐Sheng; Chen, Su Fen; Chang, Wei Chiao; Kuo, Ho-Chang

doi:10.18632/oncotarget.17700

Cited by 9 publications

(7 citation statements)

References 42 publications

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“…In our previous studies, we have shown that the changes in plasma hepcidin levels after IVIG treatment in KD patients were correlated with CAL formation and IVIG resistance [14]. We also demonstrated that prior to IVIG administration, the hepcidin levels were positively correlated with AST and ALT and negatively correlated with albumin in KD patients [15]. However, few studies have investigated the regulation of HAMP genes at the epigenetic level.…”

Section: Discussionmentioning

confidence: 87%

“…Hepcidin, which is encoded by the HAMP gene, is well known to play a key role in the inflammation-associated anemia mechanism [12,13]. Furthermore, we have demonstrated that hepcidin levels are elevated in KD patients [14,15]. Following IVIG administration, KD patients' plasma hepcidin levels significantly decreased, and their changes were related to IVIG treatment resistance and CAL formation development [8,14].…”

Section: Introductionmentioning

confidence: 79%

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HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease

Huang

Kuo

et al. 2018

Journal of Molecular and Cellular Cardiology

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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.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 79%

HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease

Huang

Kuo

et al. 2018

Journal of Molecular and Cellular Cardiology

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“…Our previous study focusing on patients with Kawasaki disease also showed that plasma hepcidin levels both before and after IVIG treatment were positively correlated with patients' length of hospital stays (R Z 0.217, p Z 0.046, and R Z 0.381, p < 0.0001, respectively). 34 In cardiac surgical patients, plasma hepcidin concentration related to outcome and preoperative anemia was shown to be associated with prolong intensive care unit stays. 35,36 Elevated hepcidin levels indicates an iron deficiency and anemia that are often associated with an increased hospital stay length.…”

Section: Discussionmentioning

confidence: 99%

The clinical value of plasma hepcidin levels in predicting bacterial infections in febrile children

Yan

Cai

Huang

2019

Pediatrics & Neonatology

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Background: Febrile children are often evaluated for the risk of bacterial infections in the pediatric emergency department (PER). Hepcidin is an acute phase inflammatory protein. In this study, we examined the plasma hepcidin levels in febrile children. Methods: This study was conducted at a pediatric emergency department with 123 febrile children. We measured plasma hepcidin levels using an enzyme-linked immunosorbent assay. We further evaluated clinical characteristics and routine blood tests along with the hepcidin levels. Results: We observed significantly higher plasma hepcidin levels in bacterial enteritis (p Z 0.026) and combined with urinary tract infection (p Z 0.007). Furthermore, hepcidin levels had a significantly positive correlation with CRP level and length of hospital stay (R Z 0.296, p Z 0.001 and R Z 0.213, p Z 0.018). Hepcidin levels greater than 65 ng/mL also more accurately predicted bacterial infections than values below 65 ng/mL (11.7% vs. 2.1%, Odds ratio 8.4, 95% confident interval 1.7e40.9, p Z 0.002). Conclusion: This study provides evidence that febrile children with bacterial infection have higher plasma hepcidin levels, and the values correlated with CRP level and length of hospital stay. Therefore, hepcidin values can potentially be adopted as a biomarker for identifying febrile children with bacterial infection, particularly bacterial enteritis and urinary tract infection.

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“…The three active DNA methyltransferases are DNMT1, DNMT3A, and DNMT3B, and three DNA demethylase, TET1-3, have been identified in mammals 7, 8. We have previously shown considerably increased mRNA expressions in toll-like receptors 9, hepcidin 10, 11, matrix metalloproteinases 12, inflammasome sensors of NOD-like receptors 13, and hypomethylation at the gene promoters of these genes, as well as that IVIG treatment can drastically alter these methylation patterns in the WBC cells of KD patients 9-14. Consistently, we have demonstrated that 87.8% of the most of the significant CpG markers between KD patients and controls are hypo-methylation of CpG markers by genome-wide screening on DNA methylation patterns with Illumina HumanMethylation450 (M450K) Bead-Chip microarray assay 15.…”

Section: Introductionmentioning

confidence: 91%

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

Huang¹,

Chen²,

Lo³

et al. 2019

Int. J. Med. Sci.

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Background: Kawasaki disease (KD) is the most common acute coronary vasculitis to occur in children. Although we have uncovered global DNA hypomethylation in KD, its underlying cause remains uncertain. In this study, we performed a survey of transcript levels of DNA methyltransferases and demethylases in KD patients. Materials and Methods: We recruited 145 participants for this study. The chip studies consisted of 18 KD patients that were analyzed before undergoing intravenous immunoglobulin (IVIG) treatment and at least 3 weeks after IVIG treatment, as well as 36 control subjects, using Affymetrix GeneChip® Human Transcriptome Array 2.0. An additional study of 91 subjects was performed in order to validate real-time quantitative PCR. Results: In our microarray study, the mRNA levels of DNMT1 and DNMT3A were significantly lower while TET2 was higher in acute-stage KD patients compared to the healthy controls. Through PCR validation, we observed that the expression of DNMT1 and TET2 are consistent with the Transcriptome Array 2.0 results. Furthermore, we observed significantly lower DMNT1 mRNA levels following IVIG treatment between those who developed CAL and those who did not. Conclusion: Our findings provide an evidence of DNA methyltransferases and demethylases changes and are among the first report that transient DNA hypomethylation is induced during acute inflammatory phase of Kawasaki disease.

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Correlation ofHAMPgene polymorphisms and expression with the susceptibility and length of hospital stays in Taiwanese children with Kawasaki disease

Cited by 9 publications

References 42 publications

HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease

HAMP promoter hypomethylation and increased hepcidin levels as biomarkers for Kawasaki disease

The clinical value of plasma hepcidin levels in predicting bacterial infections in febrile children

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

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