## 2 Large Cohort Transcriptome Analysis of Psoriasis  
The skin epidermal cells/keratinocytes are the main players contributing to the characteristic epidermal hyperplasia, immune response activation and recruitment of inflammatory cells, which are characteristic of the early onset of psoriasis pathogenesis [17]. A well-regulated balance of cell renewal and cell differentiation processes is essential for epidermal homeostasis [18]. This balance is impaired in chronic inflammatory diseases, such as psoriasis, leading to abnormal differentiation of keratinocytes [19]. Significant proliferation (around 80%) of keratinocytes, along with immune cell infiltration (including T-cells and macrophages) is a characteristic feature of psoriatic lesions. Induction of innate immunity pathways is one of the early onset features in psoriasis [16; 20]. All this emphasises the strong immunological component associated with its disease onset. This chronic immunological dysfunction in psoriasis is driven by immune cells, including Th1 and Th17 cells, as well as pro-inflammatory cytokines, primarily interleukin-17 (IL-17), interleukin-23 (IL-23), interleukin 22 (IL-22), tumour necrosis factor (TNF), and interferon-\(\gamma\)[21; 22]. IL-17/IL-22-producing T cells are mainly associated with the initial phases of psoriasis, while IFN-producing Th1 and Tc1 cells mostly regulate the chronic phase of the disease. In addition to the IL17/IL22/TNF-\(\alpha\)/IL-23 cytokine pathway, focus has recently shifted to the interleukin-1 (IL-1) family of cytokines, which includes interleukin-36 (IL-36) cytokine and IL-36 receptor antagonist (IL-36 Ra/IL36 RN) [23; 24]. IL-36 cytokines are mainly expressed in epithelial and immune cells, and include three agonistic pro-inflammatory cytokines (IL-36\(\alpha\), IL-36\(\beta\) and IL-36\(\gamma\)) and two anti-inflammatory cytokines that function as antagonists (IL-36 RN or IL-36 Ra and interleukin-38). All these cytokines share a common a receptor, complex IL-36R [25; 26]. Skin and serum samples of psoriatic patients reveal overexpression of IL-36\(\alpha\), IL-36\(\beta\), and IL-36\(\gamma\), showing a strong correlation between disease severity and cytokine levels [27]. Whole transcriptome analysis of lesional (LP) and non-lesional psoriasis (NLP) skin samples, in comparison with healthy control samples, found that, along with an up-regulated IL17/IL22 cytokine network, IL36G and IL36 RN were also identified as highly expressed in psoriatic lesions, with LP samples showing much stronger expression compared to NLP samples [16]. The epidermal differentiation complex (EDC) in in the chromosome 1q21 region encodes the major genes involved in epidermal differentiation [28]. These genes constitute three main families (a) the cornified envelope precursor proteins (loricrin, involucrin, and the family of late cornified envelope proteins), (b) the keratin filament-associated proteins (filaggrin, trichohydalin, repetin, hornerin, and cornulin), and (c) the S100 calcium-binding proteins; importantly, S100A7, S100A7A, S100A8, S100A9, and S100A12 [8; 29; 30]. Since altered epidermal differentiation is an important feature of psoriatic skin pathogenesis, these EDC genes are one of the most important psoriatic markers/gene candidates. Large scale gene expression studies help us to gain insight to the molecular basis underlying the disease pathogenesis and progression of psoriasis. Microarray-based studies of the psoriatic transcriptome have revealed a large number of differentially expressed genes (DEGs) in lesional and non-lesional skin [31]. The first longitudinal study was undertaken by [PERSON] et al. to understand how expression levels of a set of 159 genes and their transcripts were differentially expressed in lesional and psoriatic skin. It was found that most of these genes were involved in different aspects of gene regulation including intracellular signalling, cell cycle, transcriptional, and translational regulation [15].