Network-Based Computational Approach to Identify Delineating Common Cell Pathways Influencing Type 2 Diabetes and Diseases of Bone and Joints

Developing type 2 diabetes (T2D) can increase patient risk of developing other common diseases and exacerbate their severity, including diseases that affect bone and joints. Such comorbidity interactions are hard to study in detail by traditional endocrinological methods. Thus, we developed tissue transcript analytical approaches to identify common pathways through which these diseases can interact. We examined RNAseq and microarray transcript datasets from studies of T2D and chronic bone and joint diseases, namely rheumatoid arthritis (RA), osteoarthritis (OA), juvenile idiopathic arthritis (JIA) and low peak bone density, a key osteoporosis (OP) determinant. These datasets contained data from affected individuals and matched controls. Differentially expressed genes (DEGs) for each condition were compared with T2D DEG. Overlapping DEGs (i.e., those common to T2D and a bone or joint condition) were subjected to gene enrichment by pathway analyses and by gene ontology methods, and the results were evaluated by using SNP-disease linkage (dbGaP) and gene-disease association (OMIM) databases that indicate gene involvement in pathologies. By examining gene targets of transcription factors (TFs) and microRNA (miRNAs), we also constructed DEG-TF and DEG-miRNA interactions networks for analysis. We identified strong candidate genes in common pathways, notably including SYK, UCP3, ROR1, PPARG, BUB1, AKT2, ADCY2 and CCR5. The DEG-TF network and DEG-miRNA interactions network analyses revealed a number of TFs (GATA2, FOXC1, USF2, YY1, E2F1, JUN, RELA, CREB1, TFAP2A, NFB1) and miRNAs (mir-335-5p, mir-16-5p, mir-26b-5p, mir-124-3p, mir-218-5p, mir-98-5p, mir-29b-3p, mir-3135b, mir-29c-3p, mir-1-1) that can regulate the identified DEGs at the transcriptional and post-transcriptional levels. Thus this data-driven approach has enabled identification and validation of regulatory factors and cell pathways by which T2D may influence bone and joint conditions, which may suggest new ways to interfere with the pathogenic processes involved.