Twelve of the top-25 ranked genes in the PLSR onesample and PLSR two-sample differential models (indicated by a red asterisk) are linked in a network that is driven by glucocorticoid signaling. Glucocorticoid (GC) acting via glucocorticoid receptors (GR) has been shown to stimulate the expression of thousands of genes in human peripheral blood (Menke et al., 2012). GR is inactive when it is bound by a group of chaperone molecules that includes FKBP5 (Park et al., 2007). Active GR binds to GC response elements (GRE) in the promoters and induces the expression of GC-regulated genes, which include peripheral circadian clock genes such as PER1 and PER2 (Cuesta et al., 2015; So et al., 2009; Leliavski et al., 2015), but also in many other genes such as FKBP5 (Park et al., 2007). GR can also induce the rhythmic expression of NR1D2 (So et al., 2009). GC induces the expression of the phosphatase DUSP1 (Shah et al., 2014), which supresses the inflammatory response by inhibiting MAP kinases (Abraham and Clark, 2006). GC down-regulates the expression of the tyrosine kinase TXK, which regulates T-cell development (Petrillo et al., 2014). GR increases the activity of CEBPB (Berg et al., 2005), which is a transcription factor whose expression is increased during macrophage differentiation and mediates the expression of inflammatory mediators including CLEC4E (Akagi et al., 2010). GC reduces the expression of the metalloproteinase ADAMTS1 that regulates extracellular matrix function (Wong et al., 2016). GC inhibits WNT signaling (Naito et al., 2015). DAAM2 binds to and stabilizes DVL enhancing WNT signaling during cell development (Lee and Deneen, 2012). The MTOR signaling pathway senses nutrient stress and interacts with components of the WNT signaling pathway (Inoki et al., 2006). DDIT4 is a repressor of MTOR (Gordon et al., 2015) and is transcriptionally up-regulated by GC in response to stress and fasting (Polman et al., 2012; McGhee et al., 2009). FLT3 is a tyrosine kinase that binds to GR and potentiates its signaling (Asadi et al., 2008). FLT3 also regulates dendritic cell development by activating mTOR signaling (Chen et al., 2010). ZBTB16 is a transcriptional repressor that is enhanced by GC and regulates GC response genes and affects GC-induced apoptosis (Wasim et al., 2010, 2012).