Integrated bioinformatics analysis of potential pathway biomarkers using abnormal proteins in clubfoot

Abstract

Background As one of the most common major congenital distal skeletal abnormalities, congenital talipes equinovarus (clubfoot) affects approximately one in one thousandth newborns. Although several etiologies of clubfoot have been proposed and several genes have been identified as susceptible genes, previous studies did not further explore signaling pathways and potential upstream and downstream regulatory networks. Therefore, the aim of the present investigation is to explore abnormal pathways and their interactions in clubfoot using integrated bioinformatics analyses. Methods KEGG, gene ontology (GO), Reactome (REAC), WikiPathways (WP) or human phenotype ontology (HP) enrichment analysis were performed using WebGestalt, g:Profiler and NetworkAnalyst. Results A large number of signaling pathways were enriched e.g. signal transduction, disease, metabolism, gene expression (transcription), immune system, developmental biology, cell cycle, and ECM. Protein-protein interactions (PPIs) and gene regulatory networks (GRNs) analysis results indicated that extensive and complex interactions occur in these proteins, enrichment pathways, and TF-miRNA coregulatory networks. Transcription factors such as SOX9, CTNNB1, GLI3, FHL2, TGFBI and HOXD13, regulated these candidate proteins. Conclusion The results of the present study supported previously proposed hypotheses, such as ECM, genetic, muscle, neurological, skeletal, and vascular abnormalities. More importantly, the enrichment results also indicated cellular or immune responses to external stimuli, and abnormal molecular transport or metabolism may be new potential etiological mechanisms of clubfoot.

Integrated Bioinformatics Analysis Reveals Potential Pathway Biomarkers and Their Interactions for Clubfoot

“…However, these studies do not further explore the interactions among these genes, signaling pathways, and the gene upstream and downstream regulatory networks. Recently, we found that the results of bioinformatics analyses using abnormal proteins provided experimental evidence for previously proposed hypotheses, e.g., the abnormalities of ECM, genetic, muscle, neurological, skeletal, and vascular [ 16 ]. Additionally, cellular or immune responses to external stimulus, molecular transport and metabolism were suggested as new promising etiological mechanisms in clubfoot [ 16 ].…”

“…Recently, we found that the results of bioinformatics analyses using abnormal proteins provided experimental evidence for previously proposed hypotheses, e.g., the abnormalities of ECM, genetic, muscle, neurological, skeletal, and vascular [ 16 ]. Additionally, cellular or immune responses to external stimulus, molecular transport and metabolism were suggested as new promising etiological mechanisms in clubfoot [ 16 ]. However, the enriched results of bioinformatics analysis with abnormal genes in clubfoot were not explored.…”

“…Keywords were “(clubfeet or clubfoot or congenital talipes equinovarus) and (embryology or etiology or etiopathogenesis or genetics or genomics or pathology or pathophysiology)”. After duplicates were excluded, we then further screened these studies using the title and abstract reading according to the inclusion and exclusion criteria as described in our recently work [ 16 ]. Finally, a total of 31 studies were performed for subsequent genetic screening analysis.…”

“…The analysis was performed according to our previous work [ 16 ]. The interesting list contains 37 user IDs in which all of them are unambiguously mapped to 37 unique entrezgene IDs.…”

“…GO analysis [GO molecular function (GO: MF), GO cellular component (GO: CC), and GO biological process (GO: BP)] was performed as described previously [ 16 ]. Biological pathway databases were used Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome (REAC), WikiPathways (WP), and Human Phenotype Ontology (HP).…”