Exploration of Potential Biomarker Genes and Pathways in Kawasaki Disease: An Integrated in-Silico Approach

Abstract

Kawasaki disease (KD) is a common childhood systemic vasculitis with a special predilection for coronary arteries. Even after more than five decades of the initial description of the disease, the etiology of KD remains an enigma. This transcriptome data re-analysis study aimed to elucidate the underlying pathogenesis of KD using a bioinformatic approach to identify differentially expressed genes (DEGs) to delineate common pathways involved in KD. Array datasets from the Gene Expression Omnibus database were extracted and subjected to comparative meta-analysis for the identification of prominent DEGs. Fifteen hub genes with high connectivity were selected from these DEGs (IL1B, ITGAM, TLR2, CXCL8, SPI1, S100A12, MMP9, PRF1, TLR8, TREM1, CD44, UBB, FCER1G, IL7R, and FCGR1A). Of these 15 genes, five genes (CXCL8, FCGR1A, IL1B, TLR2, and TLR8) were found to be involved in neutrophil degranulation. To gain further insight into the molecular mechanism, a protein–protein network was established. Significantly enriched pathways based on the above-mentioned genes were mainly centered on biological regulation and signaling events. In addition, the pathway analysis also indicated that the majority of the DEGs in KD were enriched in systemic lupus erythematosus, suggesting a strong interplay between immunological and genetic factors in the pathogenesis of KD. These findings could significantly aid in identifying therapeutic targets and understanding KD biosignatures to design a biomarker panel for early diagnosis and severity of the disease.

Integrative Analysis of Clinical and Bioinformatics Databases to Reveal the Role of Peripheral Innate Immunity in Kawasaki Disease

“…Consistent with our results, it has been found that the hub gene CCR1 is an important gene in the pathogenesis of KD [15]. The hub genes TLR8 and IL1B are also closely related to neutrophil degranulation in patients with KD [68]. All available data thus provide evidence of neutrophil activation being crucial to KD pathogenesis.…”

Combination of S100A12/TLR2 signaling molecules and clinical indicators in a new predictive model for IVIG-resistant Kawasaki disease

“…A study by Wittkowski et al indicated that a reverse regulation of both soluble receptor for advanced glycation end products (sRAGE) and S100A12 might be a molecular mechanism promoting systemic inflammation 26 . Additionally, an integrated in-silico approach by Srivastava et al to explore the potential biomarker genes and pathways in KD identified S100A12 as a pivotal gene with high connectivity 27 . To our knowledge, our study is the first to establish a predictive scoring model for IVIG-resistant KD by combining S100A12/TLR2 pathway signaling molecules with clinical indicators.…”

Clinical indicators combined with S100A12/TLR2 signaling molecules to establish a new scoring model for coronary artery lesions in Kawasaki disease

“…Previously, Helmut et al [ 29 ] found that the inverse regulation of both sRAGE and its proinflammatory ligand S100A12 seemed to be a relevant molecular mechanism promoting systemic inflammation. Srivastava et al [ 30 ], in their study on an integrated in-silico approach for exploring potential biomarker genes and pathways in KD, identified S100A12 as one of the pivotal genes with high connectivity. Armaroli et al [ 9 ] identified that S100A12 was a highly expressed mediator in KD sterile inflammation.…”