Table 1.
Pathway analysis results for the rheumatoid arthritis (RA) dataset (adjusted p < 0.05).
| ID | Pathway | % RA genes | pathfindR | DAVID | SPIA | GSEA | GSEAPreranked | Brief Description |
|---|---|---|---|---|---|---|---|---|
| hsa00190 | Oxidative phosphorylation | 0 | <0.001 | 0.28157363 | – | 0.50656915 | 1 | Oxygen metabolism has an important role in the pathogenesis of RA (Hitchon and El-Gabalawy, 2004; Yang et al., 2015). |
| hsa05012 | Parkinson disease | 1.41 | <0.001 | 0.35202042 | 0.03287527 | 0.5198511 | 1 | |
| hsa03040 | Spliceosome | 0 | <0.001 | 0.19110635 | – | – | – | Autoimmune response to the spliceosome was previously reported in numerous autoimmune diseases (Hassfeld et al., 1995). |
| hsa04932 | Non-alcoholic fatty liver disease (NAFLD) | 2.01 | <0.001 | – | – | – | – | |
| hsa05010 | Alzheimer disease | 0.58 | <0.001 | 0.40188326 | 0.070524222 | 0.49685246 | 0.99091035 | |
| hsa03013 | RNA transport | 0.61 | <0.001 | 0.49158247 | 0.080862112 | – | – | |
| hsa05016 | Huntington disease | 0.52 | <0.001 | 0.24543866 | 0.03287527 | 0.5436461 | 1 | |
| hsa04064 | NF-kappa B signaling pathway | 8.42 | <0.001 | 0.634065 | 0.206122248 | – | – | NF-kB is a pivotal mediator of inflammatory responses (Liu et al., 2017b) and an important player in RA pathogenesis (Makarov, 2001). |
| hsa03010 | Ribosome | 0 | <0.001 | – | – | 0.6974111 | – | |
| hsa04714 | Thermogenesis | 0.43 | <0.001 | – | – | – | – | |
| hsa05130 | Pathogenic Escherichia coli infection | 0 | <0.001 | 0.42959791 | 0.103834432 | 0.740603 | 0.96458197 | Possibly related to generation of neo-autoantigens, molecular mimicry, and bystander activation of the immune system (Li et al., 2013) |
| hsa04659 | Th17 cell differentiation | 19.63 | <0.001 | – | – | – | – | Th17 cells play an important role in inflammation in human autoimmune arthritides, including RA (Pernis, 2009; Leipe et al., 2010). |
| hsa04921 | Oxytocin signaling pathway | 1.97 | <0.001 | – | – | – | – | |
| hsa04722 | Neurotrophin signaling pathway | 2.52 | <0.001 | 0.55824289 | 0.331277414 | – | – | Neurotrophin signaling is altered in RA (Rihl et al., 2005; Barthel et al., 2009). |
| hsa04130 | SNARE interactions in vesicular transport | 0 | <0.001 | 0.51353532 | 0.205302976 | 0.69465846 | 0.9727782 | |
| hsa04920 | Adipocytokine signaling pathway | 2.9 | <0.001 | – | 0.999995202 | – | – | The adipocytokines and the adipokine network have extensive roles in the pathogenesis of RA (Frommer et al., 2011; Del Prete et al., 2014). |
| hsa05167 | Kaposi sarcoma-associated herpes virus infection | 5.91 | <0.001 | – | – | – | – | |
| hsa04630 | JAK-STAT signaling pathway | 9.26 | <0.001 | – | 0.980050749 | – | – | Disruption of the JAK-STAT pathway is a critical event in the pathogenesis and progression of rheumatoid arthritis (Malemud, 2018). |
| hsa04931 | Insulin resistance | 1.85 | <0.001 | – | – | – | – | |
| hsa04260 | Cardiac muscle contraction | 0 | <0.001 | – | – | 0.6976311 | 1 | |
| hsa05142 | Chagas disease (American trypanosomiasis) | 7.77 | <0.001 | – | 0.999995202 | – | – | |
| hsa05100 | Bacterial invasion of epithelial cells | 1.35 | <0.001 | – | 0.743380146 | – | – | Possibly related to generation of neo-autoantigens, molecular mimicry, and bystander activation of the immune system (Li et al., 2013). |
| hsa05163 | Human cytomegalovirus infection | 4 | <0.001 | – | – | – | – | |
| hsa04660 | T cell receptor signaling pathway | 10.89 | <0.001 | – | 0.743380146 | – | – | Dysregulation of the TCR signaling pathway was previously implicated in RA biology (Sumitomo et al., 2018). |
| hsa05131 | Shigellosis | 3.08 | <0.001 | 0.51130292 | 0.137642182 | – | – | Possibly related to generation of neo-autoantigens, molecular mimicry, and bystander activation of the immune system (Li et al., 2013). |
| hsa05203 | Viral carcinogenesis | 2.99 | <0.001 | – | 0.999995202 | – | – | |
| hsa05166 | Human T-cell leukemia virus 1 infection | 7.31 | <0.001 | 0.48795724 | 0.137642182 | – | – | |
| hsa04210 | Apoptosis | 1.47 | <0.001 | – | 0.827952041 | – | – | Apoptosis may play divergent roles in RA biology (Liu and Pope, 2003). |
| hsa05165 | Human papillomavirus infection | 1.82 | <0.001 | – | – | – | – | |
| hsa05161 | Hepatitis B | 6.13 | <0.001 | – | – | – | – | |
| hsa04150 | mTOR signaling pathway | 0.66 | 0.001061744 | – | 0.743380146 | – | – | Intracellular signaling pathway (including mTOR signaling) play a critical role in rheumatoid arthritis (Malemud, 2013; Malemud, 2015). |
| hsa05418 | Fluid shear stress and atherosclerosis | 1.44 | 0.001166905 | – | – | – | – | |
| hsa04218 | Cellular senescence | 2.5 | 0.001351009 | – | – | – | – | |
| hsa04217 | Necroptosis | 4.32 | 0.001442161 | – | – | – | – | Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production (Kearney et al., 2015). |
| hsa04145 | Phagosome | 5.26 | 0.001665316 | 0.49641734 | – | – | – | |
| hsa03050 | Proteasome | 2.22 | 0.001881322 | – | – | 0.7889826 | – | Proteasome modulates immune and inflammatory responses in autoimmune diseases (Wang and Maldonado, 2006). |
| hsa05168 | Herpes simplex infection | 8.65 | 0.002442405 | – | 0.53977679 | – | – | |
| hsa05200 | Pathways in cancer | 4.56 | 0.002463658 | – | 0.743380146 | – | – | |
| hsa04621 | NOD-like receptor signaling pathway | 5.06 | 0.002477183 | – | 0.909381246 | – | – | NOD-like receptors are being implicated in the pathology of RA and other rheumatic diseases (McCormack et al., 2009). |
| hsa05202 | Transcriptional misregulation in cancer | 4.84 | 0.002495122 | – | 0.743380146 | – | – | |
| hsa04151 | PI3K-Akt signaling pathway | 2.82 | 0.00331152 | – | – | – | – | PI3K-Akt signaling regulates diverse cellular processes and was proposed as a target for inducing cell death in RA (Malemud, 2015). |
| hsa05215 | Prostate cancer | 1.03 | 0.003884234 | – | 0.999995202 | – | – | |
| hsa05170 | Human immunodeficiency virus 1 infection | 3.3 | 0.004185672 | – | – | – | – | |
| hsa04066 | HIF-1 signaling pathway | 5 | 0.004382877 | – | – | – | – | Alterations in hypoxia-related signaling pathways are considered potential mechanisms of RA pathogenesis (Quiñonez-Flores et al., 2016). |
| hsa05225 | Hepatocellular carcinoma | 3.57 | 0.004782642 | – | – | – | – | |
| hsa04922 | Glucagon signaling pathway | 0 | 0.004927201 | – | – | – | – | |
| hsa03420 | Nucleotide excision repair | 0 | 0.005418059 | 0.63260927 | – | – | – | DNA damage load is higher in RA patients, thus activating repair pathways (Lee et al., 2003). |
| hsa04015 | Rap1 signaling pathway | 0.97 | 0.005543915 | – | – | – | – | Deregulation of Rap1 signaling pathway was shown to be a critical event altering the response of synovial T cells in RA (Remans et al., 2002). |
| hsa05221 | Acute myeloid leukemia | 3.03 | 0.006008327 | – | 0.999995202 | – | – | |
| hsa05132 | Salmonella infection | 3.49 | 0.006557353 | – | 0.721697645 | – | – | Possibly related to generation of neo-autoantigens, molecular mimicry, and bystander activation of the immune system (Li et al., 2013). |
| hsa05212 | Pancreatic cancer | 4 | 0.006646458 | – | 0.743380146 | – | – | |
| hsa04662 | B cell receptor signaling pathway | 2.82 | 0.00748718 | – | 0.851804025 | – | – | |
| hsa04971 | Gastric acid secretion | 4 | 0.008829291 | – | 0.743380146 | – | – | |
| hsa04020 | Calcium signaling pathway | 3.19 | 0.009304653 | – | 0.999995202 | – | – | Dysregulation of the calcium signaling pathway was implicated in RA pathogenesis (Berridge, 2016). |
| hsa04919 | Thyroid hormone signaling pathway | 3.45 | 0.009478272 | – | – | – | – | |
| hsa05220 | Chronic myeloid leukemia | 3.95 | 0.011899647 | – | 0.743380146 | – | – | |
| hsa04728 | Dopaminergic synapse | 1.53 | 0.012701709 | – | 0.743380146 | – | – | |
| hsa05412 | Arrhythmogenic right ventricular cardiomyopathy (ARVC) | 1.39 | 0.012829444 | – | 0.96639695 | – | – | |
| hsa04371 | Apelin signaling pathway | 1.46 | 0.015134748 | – | – | – | – | |
| hsa04910 | Insulin signaling pathway | 0 | 0.015134748 | – | 0.999995202 | – | 0.95215786 | |
| hsa03015 | mRNA surveillance pathway | 0 | 0.015767824 | – | – | – | – | |
| hsa04658 | Th1 and Th2 cell differentiation | 17.39 | 0.016291789 | – | – | – | – | RA patients were characterized by a disruption of Th1/Th2 balance towards Th1(He et al., 2017). |
| hsa04620 | Toll-like receptor signaling pathway | 5.77 | 0.017712009 | – | 0.743380146 | 0.72964895 | 1 | Toll-like receptors are being implicated in the pathology of RA and other rheumatic diseases (McCormack et al., 2009). |
| hsa05410 | Hypertrophic cardiomyopathy (HCM) | 2.41 | 0.019642576 | – | – | – | – | |
| hsa04668 | TNF signaling pathway | 5.45 | 0.0209396 | – | – | – | – | Intracellular signaling pathway (including TNF signaling) play a critical role in rheumatoid arthritis (Malemud, 2013). |
| hsa05169 | Epstein-Barr virus infection | 8.96 | 0.022925676 | – | 0.743380146 | – | – | |
| hsa05031 | Amphetamine addiction | 2.94 | 0.023901842 | – | 0.743380146 | – | – | |
| hsa05414 | Dilated cardiomyopathy (DCM) | 2.22 | 0.025016113 | – | 0.851804025 | – | – | |
| hsa04012 | ErbB signaling pathway | 2.35 | 0.026253837 | – | 0.999995202 | – | – | Intracellular signaling pathway play a critical role in rheumatoid arthritis (Malemud, 2013). |
| hsa04510 | Focal adhesion | 0.5 | 0.02805129 | – | 0.999995202 | 0.77597433 | – | Adhesion molecules have an important role in RA (Pitzalis et al., 1994). |
| hsa04110 | Cell cycle | 4.03 | 0.029916503 | – | 0.743380146 | – | – | Cell cycle stalling was recently linked to arthritis (Matsuda et al., 2017). |
| hsa05206 | MicroRNAs in cancer | 1.34 | 0.03026234 | – | – | – | – | |
| hsa03460 | Fanconi anemia pathway | 0 | 0.033094195 | – | 0.743380146 | – | – | DNA damage load is higher in RA patients, thus activating repair pathways (Lee et al., 2003). |
| hsa05160 | Hepatitis C | 3.23 | 0.035219047 | – | 0.743380146 | – | – | |
| hsa04721 | Synaptic vesicle cycle | 1.28 | 0.035442941 | – | – | – | – | |
| hsa04810 | Regulation of actin cytoskeleton | 0.47 | 0.036496481 | – | 0.96639695 | 0.80830806 | – | Actin cytoskeleton dynamics is linked to synovial fibroblast activation (Vasilopoulos et al., 2007). Autoimmune response to cytoskeletal proteins (including actin) was reported in RA (Shrivastav et al., 2002). |
| hsa04270 | Vascular smooth muscle contraction | 2.48 | 0.036862558 | – | 0.070524222 | – | 1 | |
| hsa05230 | Central carbon metabolism in cancer | 1.54 | 0.038909519 | – | – | – | – | Dysregulation of energy metabolism is indicated in RA (Yang et al., 2015). |
“ID” indicates the Kyoto Encyclopedia of Genes and Genomes (KEGG) ID for the enriched pathway, whereas “Pathway” indicates the KEGG pathway name. “% RA genes” indicates the percentage of RA genes in the pathway. The lowest Bonferroni-adjusted p value for pathfindR analysis is provided in “pathfindR,” the false discovery rate (FDR)-adjusted p value for Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis is provided in “DAVID,” the FDR-adjusted p value for Signaling Pathway Impact Analysis (SPIA) is presented in “SPIA,” and the FDR-adjusted p values for Gene Set Enrichment Analysis (GSEA) and GSEAPreranked are presented in“GSEA” and “GSEAPreranked,” respectively. Significant p values (i.e., adjusted p value <0.05) are given in bold font. “-“ indicates the pathway was not found to be enriched by the given tool. If a pathway is relevant to RA, a brief description of its relevance is provided in “Brief Description.”