Overview of the workflow used to identify protein clusters of functional importance in rheumatoid factor-negative (RF-ve) polyarticular and oligoarticular juvenile idiopathic arthritis (JIA). This figure outlines each of the steps taken and gives cross references to the specific tables and figures that provide further details of that particular step in the process. (A) JIA genetic association data of replicated single nucleotide polymorphisms (SNPs) associated with RF-ve polyarticular JIA or oligoarticular JIA and JIA genome-wide association data findings were ascertained. SNPs were mapped to genes using Gene Relationships Across Implicated Loci (GRAIL) software (n = 348) (Additional file 1: Table S1A and B). (B) A JIA interactome network model (JIA Interactome) was inferred from JIA-associated genes using the BioGRID database (Figure 2A). (Bi) The top 10% of nodes, ranked by connectivity and bottlenecks, were used to derive a minimal essential network (MEN) of 248 genes (Figure 2B and Additional file 3: Table S3A). The Reactome database and spectral partition clustering was used to determine clusters of genes within the MEN (Figure 2C). (Bii) The Disease Association Protein-Protein Link Evaluator (Dapple) algorithm was used to identify Highly Connected Genes (Figure 3 and Additional file 3: Table S3B). The overlap of genes between Bi and Bii was determined (n = 26 genes) (Additional file 3: Table S3B). (C)
JIA gene expression data from published sources, collated from the Gene Expression Omnibus database (GEO) (Additional file 2: Table S2 and Additional file 4: Table S4, Additional file 5: Table S5, Additional file 6: Table S6), was integrated with the overlap of the genes from Bi and Bii. (D) A prioritised list of JIA-associated genes with functionally associated network properties was identified from the integration of JIA genetic association and gene expression data (n = 3 genes) (Table 2). (E) MCODE was used to determine RF-ve polyarticular and oligoarticular JI-specific network clusters, protein:protein interactions of functional relevance (Figure 4A and B). GWAS, genome-wide association studies.