The shared crosstalk of multiple pathways involved in the inflammation between rheumatoid arthritis and coronary artery disease based on a digital gene expression profile

Abstract

Rheumatoid arthritis (RA) and coronary artery disease (CAD) are both complex inflammatory diseases, and an increased prevalence of CAD and a high rate of mortality have been observed in RA patients. But the molecular mechanism of inflammation that is shared between the two disorders is unclear. High-throughput techniques, such as transcriptome analysis, are becoming important tools for genetic biomarker discovery in highly complex biological samples, which is critical for the diagnosis, prognosis, and treatment of disease. In the present study, we reported one type of transcriptome analysis method: digital gene expression profiling of peripheral blood mononuclear cells of 10 RA patients, 10 CAD patients and 10 healthy people. In all, 213 and 152 differently expressed genes (DEGs) were identified in RA patients compared with normal controls (RA vs. normal) and CAD patients compared with normal controls (CAD vs. normal), respectively, with 73 shared DEGs between them. Using this technique in combination with Ingenuity Pathways Analysis software, the effects on inflammation of four shared canonical pathways, three shared activated predicted upstream regulators and three shared molecular interaction networks were identified and explored. These shared molecular mechanisms may provide the genetic basis and potential targets for optimizing the application of current drugs to more effectively treat these diseases simultaneously and for preventing one when the other is diagnosed.

Figure 1. Gene expression in groups of RA vs. normal, CAD vs. normal and shared DEGs.

A: Venn diagram showing the number of uniquely up-regulated (red) or down-regulated (green) genes comparing individuals with RA and CAD to normal persons and shared DEGs; B: Bar diagram indicating number of DEGs in the RA vs. normal and the CAD vs. normal groups and the shared DEGs between them.

Figure 2. The shared functions of DEGs in individuals with RA and CAD compared to normal controls.

Radar diagrams show the shared functions of DEGs in RA and CAD compared to normal controls in aspects of ‘Diseases and disorder’, ‘Molecular and cellular functions’, and ‘Physiological system development and function’. Blue areas represented the number of DEGs in RA vs. the normal number involved in the functions. Red areas represent the number of DEGs in CAD vs. normal controls involved in the functions.

Figure 3. Network, molecular functions and canonical pathway analysis of shared DEGs in RA vs. normal and CAD vs. normal individuals.

A: The molecular network of 95 shared DEGs in RA vs. normal and CAD vs. normal individuals; blue molecules represent the shared DEGs; B: the top 4 shared canonical pathways (with score (-log (p-value))>1.3, p-value of pathway <0.05) related with inflammation which 95 shared DEGs in RA vs. normal and CAD vs. normal involved in: IL-8 signaling; antigen presentation pathway; OX40 signaling pathway; TREM1 signaling; C: the function classification of shared DEGs in both RA vs. normal and CAD vs. normal, the number in the bar diagram represented the DEGs numbers participated in the corresponding pathways.

Figure 4. The significant commonly shared signaling canonical pathways between RA and CAD involved in inflammation.

A: IL-8 signaling; B: antigen presentation pathway; C: OX40 signaling pathway; D: TREM1 signaling; E: picture legends. Purple circle: the same genes involved in the commonly shared pathways in RA and CAD.

Figure 5. The shared molecular networks and upstream regulators networks of RA and CAD.

A: shared associated network (SAN) -1; B: SAN-2; C: SAN-3; D: the network of upstream regulators and target molecules of DEGs in RA; E: the network of upstream regulators and target molecules of DEGs in CAD; F: the legends of predicted networks. In A, B and C, the molecules with orange circles stand for shared molecules between RA and CAD.

Figure 6. The summary view of shared pathways related with shared DEGs in RA and CAD involved in inflammation.

The molecules with red color represent the shared DEGs in both RA vs. normal and CAD vs. normal; molecules with italics in pink shapes represent the shared upstream regulators in both RA vs. normal and CAD vs. normal.