Increased Risk of Atopic Dermatitis in Preschool Children with Kawasaki Disease: A Population-Based Study in Taiwan

Chang

Arthritis & Rheumatology

et al. 2015

Self Cite

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.Kawasaki disease (KD) is an acute febrile systemic vasculitis first described by Kawasaki et al (1) in English in 1974. The most serious complication of KD is the formation of coronary artery lesions, including myocardial infarction, coronary artery fistula, coronary artery dilatation, and aneurysm (2). In developed countries, it is the leading cause of acquired heart disease in children; however, its etiology remains unknown (3-6). KD mainly affects children younger than 5 years of age, especially those in Asian countries, but its incidence has increased worldwide.

Section: Discussionmentioning

confidence: 83%

Identification of an Association Between Genomic Hypomethylation of FCGR2A and Susceptibility to Kawasaki Disease and Intravenous Immunoglobulin Resistance by DNA Methylation Array

Chang

Arthritis & Rheumatology

et al. 2015

Self Cite

“…This protease plays a key role in profilaggrin-filaggrin processing and reduced expression in mice leads to an eczema phenotype [ 34 ]. It is of interest that eczema is over-represented among patients with KD and perhaps genetic variants in this gene may contribute to this phenotype [ 35 , 36 ]. However, the association with CAA is unclear as expression is claimed to be limited to the skin [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Global gene expression profiling identifies new therapeutic targets in acute Kawasaki disease

et al. 2014

BackgroundGlobal gene expression profiling can provide insight into the underlying pathophysiology of disease processes. Kawasaki disease (KD) is an acute, self-limited vasculitis whose etiology remains unknown. Although the clinical illness shares certain features with other pediatric infectious diseases, the occurrence of coronary artery aneurysms in 25% of untreated patients is unique to KD.MethodsTo gain further insight into the molecular mechanisms underlying KD, we investigated the acute and convalescent whole blood transcriptional profiles of 146 KD subjects and compared them with the transcriptional profiles of pediatric patients with confirmed bacterial or viral infection, and with healthy control children. We also investigated the transcript abundance in patients with different intravenous immunoglobulin treatment responses and different coronary artery outcomes.ResultsThe overwhelming signature for acute KD involved signaling pathways of the innate immune system. Comparison with other acute pediatric infections highlighted the importance of pathways involved in cell motility including paxillin, relaxin, actin, integrins, and matrix metalloproteinases. Most importantly, the IL1β pathway was identified as a potential therapeutic target.ConclusionOur study revealed the importance of the IL-1 signaling pathway and a prominent signature of innate immunity and cell migration in the acute phase of the illness.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0102-6) contains supplementary material, which is available to authorized users.

“…In addition, predisposing loci related to immune activation, inflammation, T cell receptor signaling, regulation of proinflammatory cytokines, and antibody-mediated immune responses have also been described in Asian children with KD 12 13 15 16 . It has been further noted through population-based studies in Taiwan that children with KD tend to have higher risks of subsequent allergic susceptibilities including atopic dermatitis (AD), allergic rhinitis (AR), asthma, and urticaria after KD illness 17 18 19 20 . These KD predisposing loci might also contribute to determinants of allergic disease with distinct immune phenotypes.…”

mentioning

confidence: 99%

Genetic variants in PLCB4/PLCB1 as susceptibility loci for coronary artery aneurysm formation in Kawasaki disease in Han Chinese in Taiwan

Lin

Chang

Liu

et al. 2015

Sci Rep

Kawasaki disease (KD) is an acute, inflammatory, and self-limited vasculitis affecting infants and young children. Coronary artery aneurysm (CAA) formation is the major complication of KD and the leading cause of acquired cardiovascular disease among children. To identify susceptible loci that might predispose patients with KD to CAA formation, a genome-wide association screen was performed in a Taiwanese KD cohort. Patients with both KD and CAA had longer fever duration and delayed intravenous immunoglobulin treatment time. After adjusting for these factors, 100 susceptibility loci were identified. Four genes were identified from a single cluster of 35 using the Ingenuity Pathway Analysis (IPA) Knowledge Base. Silencing KCNQ5, PLCB1, PLCB4, and PLCL1 inhibited the effect of lipopolysaccharide-induced endothelial cell inflammation with varying degrees of proinflammatory cytokine expression. PLCB1 showed the most significant inhibition. Endothelial cell inflammation was also inhibited by using a phospholipase C (PLC) inhibitor. The single nucleotide polymorphism rs6140791 was identified between PLCB4 and PLCB1. Plasma PLC levels were higher in patients with KD and CC+CG rs6140791genotypes, and these genotypes were more prevalent in patients with KD who also had CAA. Our results suggest that polymorphism of the PLCB4/B1 genes might be involved in the CAA pathogenesis of KD.