## 2 Large Cohort Transcriptome Analysis of Psoriasis
Enrichment analysis revealed two networks PP01 and PP02 linked to different biochemical pathways for the two lesional psoriatic subgroups. PP01 network cluster was associated with Notch, Wnt, TGF\(\beta\), and ERbB signalling pathways, while PP02 was enriched with metabolic pathways. This suggested that therapies targeting these pathways could be employed for the respective subgroups [43]. One large scale study, involving 85 matched pairs of lesional and non-lesional biopsies from patients, was performed by [PERSON] et al. and identified 2725 differentially expressed genes in psoriatic plaques. In agreement with many previous studies, S100 family of proteins and SERPINs were the strongly upregulated genes, along with many peptidases, including Kallikrein-related peptidase-6 (KLK6) and kallikrein-related peptidase-13 (KLK13) [44; 45; 46]. Many genes associated with lipid and fatty acid metabolism, as well as chemokines CCL27, were down regulated in these plaques [44]. A potential linkage between psoriatic skin gene expression and co-morbidities was reported in patients with moderate-to-severe psoriatic compared with healthy controls. Serum profiles identified strong association between functional pathways in lesional skin with diabetes and cardiovascular risk pathways [46]. Several new DEGs, not reported in previous microarray studies, were found from another large scale RNA-seq analysis from lesional skin biopsies from 174 individuals [31]. This comprehensive study by [PERSON] et al. made an interesting observation, that, although RNA-seq and microarray measurements were consistent for intermediate and high abundance transcripts, several discrepancies were noticed for low abundance transcripts in both disease groups cases controls. The gene fold change (FC) also showed wider estimates for low abundance transcripts [31]. Interferons (IFNs) are one of the key players in psoriasis pathogenesis and have been found in psoriatic lesions, emphasising the importance of these cytokines in this disease [47; 48]. Whole genome array analysis from paired lesional and non-lesional psoriatic skin have demonstrated that type I IFNs and type II IFN-inducible genes are strongly expressed in psoriatic skin. The mRNAs of type I IFN family members-IFNAR1, and IFNAR2 are upregulated in lesional skin, but not in non-lesional skin (except IFN-a5 and IFN-k). A significant expression of type 1 IFN-inducible genes, along with IFN-\(\gamma\) (which is a Type II IFN) and TNF-\(\alpha\) in lesional skin (but not in non-lesional skin), was also observed in psoriatic patients examined in this study [47]. The upregulation of mRNAs of type I IFNs, IFN-\(\gamma\), and TNF-\(\alpha\) gene signatures in lesional skin suggests the presence of these cytokines and their active signalling in psoriasis, making it a potential therapeutic target for psoriasis treatment. In contrast, the elevated expression of mRNAs of IFN-\(\gamma\) or TNF-\(\alpha\) did not correspond to upregulation of IFN-\(\gamma\) or TNF-\(\alpha\)-inducible genes, suggesting their absence in non-lesional skin, or that other signalling molecules might have inhibitory effects on the IFN-\(\gamma\) and TNF-\(\alpha\) pathways in non-lesional skin of psoriatic patients [47]. A separate study by one of the above mentioned authors found that a single injection of IFN-\(\gamma\) to the dermis of non-lesional sites of psoriasis can recapitulate psoriasis immune response and the transcriptional profile changes in psoriatic plaques [45]. Similar influx was also observed in healthy, non- psoriatic individuals [49]. Great variability in treatment response exists between individual psoriatic patients, reflecting the heterogeneity of various inflammatory networks driving the disease. Psoriasis lesions looks clinically similar, with their characteristic pathophysiological features, with standard immunohistochemistry unable to differentiate between lesional skin samples. It is now possible to identify such variability using whole genome transcriptomic profiling.