Systems Analysis of Avascular Necrosis of Femoral Head Using Integrative Data Analysis and Literature Mining Delineates Pathways Associated with Disease

Avascular necrosis of femoral head (AVNFH) is a debilitating disease, which affects the middle aged population. Though the disease is managed using bisphosphonate, it eventually leads to total hip replacement due to collapse of femoral head. Studies regarding the association of single nucleotide polymorphisms with AVNFH, transcriptomics, proteomics, metabolomics, biophysical, ultrastructural and histopathology have been carried out. Functional validation of SNPs was carried out using literature. An integrated systems analysis using the available datasets might help to gain further insights into the disease process. We have carried out an analysis of transcriptomic data from GEO-database, SNPs associated with AVNFH, proteomic and metabolomic data collected from literature. Based on deficiency of vitamins in AVNFH, an enzyme-cofactor network was generated. The datasets are analyzed using ClueGO and the genes are binned into pathways. Metabolomic datasets are analyzed using MetaboAnalyst. Centrality analysis using CytoNCA on the data sets showed cystathionine beta synthase and methylmalonyl-CoA-mutase to be common to 3 out of 4 datasets. Further, the genes common to at least two data sets were analyzed using DisGeNET, which showed their involvement with various diseases, most of which were risk factors associated with AVNFH. Our analysis shows elevated homocysteine, hypoxia, coagulation, Osteoclast differentiation and endochondral ossification as the major pathways associated with disease which correlated with histopathology, IHC, MRI, Micro-Raman spectroscopy etc. The analysis shows AVNFH to be a multi-systemic disease and provides molecular signatures that are characteristic to the disease process.