| Summary: | The runt-related transcription factor 3 (RUNX3) regulates the differentiation of monocytes and their response to inflammation. However, the transcriptomic context of <i>RUNX3</i> expression in blood monocytes remains poorly understood. We aim to learn about <i>RUNX3</i> from its relationships within transcriptomes of bulk CD14+ cells in adults. This study used immunomagnetically sorted CD14+ cell gene expression microarray data from the Multi-Ethnic Study of Atherosclerosis (MESA, n = 1202, GSE56047) and the Correlated Expression and Disease Association Research (CEDAR, n = 281, E-MTAB-6667) cohorts. The data were preprocessed, subjected to <i>RUNX3</i>-focused correlation analyses and random forest modeling, followed by the gene ontology analysis. Immunity-focused differential ratio analysis with intermediary inference (DRAIMI) was used to integrate the data with protein–protein interaction network. Correlation analysis of <i>RUNX3</i> expression revealed the strongest positive association for <i>EVL</i> (r<sub>mean</sub> = 0.75, p<sub>FDR-MESA</sub> = 5.37 × 10<sup>−140</sup>, p<sub>FDR-CEDAR</sub> = 5.52 × 10<sup>−80</sup>), <i>ARHGAP17</i> (r<sub>mean</sub> = 0.74, p<sub>FDR-MESA</sub> = 1.13 × 10<sup>−169</sup>, p<sub>FDR-CEDAR</sub> = 9.20 × 10<sup>−59</sup>), <i>DNMT1</i> (r<sub>mean</sub> = 0.74, p<sub>FDR-MESA</sub> = 1.10 × 10<sup>−169</sup>, p<sub>FDR-CEDAR</sub> = 1.67 × 10<sup>−58</sup>), and <i>CLEC16A</i> (r<sub>mean</sub> = 0.72, p<sub>FDR-MESA</sub> = 3.51 × 10<sup>−154</sup>, p<sub>FDR-CEDAR</sub> = 2.27 × 10<sup>−55</sup>), while the top negative correlates were <i>C2ORF76</i> (r<sub>mean</sub> = −0.57, p<sub>FDR-MESA</sub> = 8.70 × 10<sup>−94</sup>, p<sub>FDR-CEDAR</sub> = 1.31 × 10<sup>−25</sup>) and <i>TBC1D7</i> (r<sub>mean</sub> = −0.55, p<sub>FDR-MESA</sub> = 1.36 × 10<sup>−69</sup>, p<sub>FDR-CEDAR</sub> = 7.81 × 10<sup>−30</sup>). The <i>RUNX3</i>-associated transcriptome signature was involved in mRNA metabolism, signal transduction, and the organization of cytoskeleton, chromosomes, and chromatin, which may all accompany mitosis. Transcriptomic context of <i>RUNX3</i> expression in monocytes hints at its relationship with cell growth, shape maintenance, and aspects of the immune response, including tyrosine kinases.
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