Rheumatoid Arthritis CORE INTERACTOME

Curated collection of molecules from high-throughput screens of diverse (multi-omic) biochemical origin, experimentally associated to RA. Starting from such collection the RA-related protein-protein interaction (PPI) networks (interactomes)based on experimental PPI data have been generated.
The datasets used to construct the map are gathered from 13 different sources from databases and literature (Table 1). We included molecules experimentally associated to RA from manual curation of literature sources (core dataset, CD, 377 proteins), and additional molecules and pathways strongly yet not explicitly associated to RA (extended dataset, ED, 4709 proteins).
The CD is composed of 377 proteins retrieved from six data sources (Data Sheet 1, Tables S1–S6):
1) RA genome-wide association studies (GWAS) gathered and integrated from five different databases (BioGPS (Wu et al., 2009), HuGE (Yu et al., 2008), NHGRI, OMIM, PharmGKB (Klein et al., 2001); see Data Sheet 1, Table S1 for the specific query processes);
2) RA-associated proteins from the Universal Protein Resource (Uniprot) (Consortium, 2010), retrieved using as search parameters “rheumatoid arthritis” and “human” and then manually screened (Data Sheet 1, Table S2);
3) Genes and proteins retrieved from a comprehensive review of the literature, in particular genes appearing in Tables 1, 2of Review (Mcinnes and Schett, 2011) and cited references (Data Sheet 1, Table S3);
4) Genes that show epigenetic changes in relation to RA, as specified in Trenkmann et al. (2010); Karouzakis et al. (2011)(Data Sheet 1, Table S4);
5) Proteins that are at the interface between the host and the oral microbiome, in particular proteins experimentally known to be differentially expressed in presence of Porphyromonas Gingivalis(Zhou and Amar, 2006), a periodontitis-causing bacterium that has been strongly linked to the insurgence of RA (Mikuls et al., 2012; Scher et al., 2012; Smit et al., 2012; Bingham and Moni, 2013; Ogrendik, 2013; Okada et al., 2013) (Data Sheet 1, Table S5);
6) The key elements of the NF-κB system, the master regulator of inflammation (Oeckinghaus et al., 2011; Smale, 2011; Hayden and Ghosh, 2012) at the center of a complex regulatory interactome (Tieri et al., 2012) prominently implicated in the onset and development of RA (Miagkov et al., 1998; Makarov, 2001; Feldmann et al., 2002; Okamoto, 2006; Roman-Blas and Jimenez, 2006, 2008; Simmonds and Foxwell, 2008; Van Loo and Beyaert, 2011): we included 16 “consensus” proteins that appear at the intersection of the three main NF-κB-related datasets described in Tieri et al. (2012)(Data Sheet 1, Table S6).
Datasets are integrated at the PPI level as peers to avoid introducing any bias a prioriin the network construction and to warrant that these data are connected in a biologically meaningful way. Protein-protein interactions were retrieved in Cytoscape from the Agile Protein Interaction DataAnalyzer database (APID, Prieto and De Las Rivas, 2006) that includes all known experimentally validated protein-protein interactions from BIND, BioGRID, DIP, HPRD, IntAct and MINT databases, accessed via the APID2NET (Hernandez-Toro et al., 2007) plugin. This process lead to the definitions of, respectively, the core interactome (CI, 303 proteins, 597 interactions, high resolution Image S1) and the extended interactome (EI, 3783 proteins, 24457 interactions, high resolution Image S2). Discussion on caveats and choices of original sources can be found in Tieri and Nardini (2013).