RESUMEN
BACKGROUND: Kawasaki disease (KD) is associated with expression and methylation of Fc gamma receptor genes. We characterized immunoglobulin A (IgA), IgE, IgG, and IgM receptor expression levels in KD. METHODS: Fc receptor expression levels were characterized using GeneChip Human Transcriptome Array 2.0 (HTA 2.0) with 18 KD patients, 18 non-febrile controls, and 18 febrile controls. Another 48 control individuals and 46 patients with KD were measured using pyrosequencing for the methylation levels. RESULTS: The mRNA expression levels of FCER1A and FCER2 were significantly lower in KD patients than in non-febrile controls and then rose following treatments with intravenous immunoglobulin (IVIG). Expression levels of FCER1G increased compared to the non-febrile subjects and then subsided after IVIG. FCER1A methylation was significantly lower among KD patients and even lower in KD patients with IVIG resistance. HTA analysis revealed higher mRNA levels of FCAR, FCGR1C, and FCGR2A in KD patients. FCMR mRNA expression levels were significantly lower in KD patients. FCMR expression levels rose after IVIG treatment. After IVIG, FCGR1A, B, and C decreased even lower than the febrile controls. CONCLUSION: This is the first study indicating that IgA, IgE, IgG, and IgM receptors are associated with KD. We highlighted potential biomarkers related to Fc receptors and their regulation.
Asunto(s)
Síndrome Mucocutáneo Linfonodular/genética , Receptores Fc/genética , Receptores de IgE/genética , Transcriptoma , Estudios de Casos y Controles , Preescolar , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Lactante , Masculino , Síndrome Mucocutáneo Linfonodular/diagnóstico , Síndrome Mucocutáneo Linfonodular/tratamiento farmacológico , Síndrome Mucocutáneo Linfonodular/inmunología , Receptores Fc/metabolismo , Receptores de IgE/metabolismo , Receptores de IgG/genética , Receptores de IgG/metabolismo , Factores de Tiempo , Resultado del TratamientoAsunto(s)
MicroARNs/genética , Síndrome Mucocutáneo Linfonodular/genética , Estudios de Casos y Controles , Preescolar , Diagnóstico Precoz , Femenino , Marcadores Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , MicroARNs/sangre , Síndrome Mucocutáneo Linfonodular/sangre , Síndrome Mucocutáneo Linfonodular/diagnóstico , Análisis de Secuencia de ARN , Máquina de Vectores de SoporteRESUMEN
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 ß-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 ß-catenin, which may be involved in both the cause and the development of KD.