Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis

Abstract

Psoriasis is a complex disease with an expanding definition of its pathological features. We sought to expand/refine the psoriasis transcriptome using 85 paired lesional and non-lesional samples from a cohort of patients with moderate-to-severe psoriasis vulgaris who were not receiving active psoriasis therapy. This new analysis identified 4,175 probe sets (representing 2,725 unique known genes) as being differentially expressed in psoriasis lesions compared with matched biopsies of non-lesional skin when the following criteria were applied: >2-fold change and false discovery rate <0.05. These probe sets represent the largest and most comprehensive set of genes defining psoriasis at the molecular level and within the previously unidentified genes, a link to functional pathways associated with metabolic diseases/diabetes and to cardiovascular risk pathways is identified. In addition, we profiled the serum of moderate-to-severe psoriatics compared with healthy controls to assess the overlap of overexpressed lesional genes with overexpressed systemic proteins. We identified linkage of functional pathways in lesional skin associated with metabolic diseases/diabetes and cardiovascular risk with those pathways overexpressed in the serum, suggesting a potential linkage between altered gene transcription in the skin and comorbidities commonly seen in patients with moderate-to-severe psoriasis.

Figure 1

The transcriptome of moderate-to-severe psoriasis. (a) Heatmap of differentially expressed genes (DEGs). Unsupervised clustering of lesional (LS) versus non-lesional (NL) DEGs. (b) Scatter plot of the estimated fold change (log2 scale) by real-time reverse transcriptase PCR (RT-PCR, x-axis) and gene array (y-axis) for a selected group of 50 genes (see Table 3). Gray lines outline the two-fold change (FCH) regions. Stars and bullets represent two different low-density cards. Red shows confirmed genes. Classical linear regression analysis (red line) shows a slight compression of FCHs by gene array. Pearson's (r) and Spearman's (ρ) correlation values are presented along with P-values. (c) Venn diagram comparing genes (blue numbers: downregulated genes; red numbers: upregulated genes) identified in this study with those of two published studies employing the same Affymetrix HG U133 Plus 2.0 arrays using the same cutoff criteria (false discovery rate <0.05, FCH>2).

Figure 2

Protein expression of previously unreported genes detected in this transcriptome. Representative immunohistochemistry staining in normal, non-lesional, and lesional psoriasis skin (n=5). (a) Renin was highly expressed by scattered cells in the papillary and upper reticular dermis mostly in lesional skin compared with non-lesional and normal skin. (b) Cytotoxic T-lymphocyte antigen (CTLA4) was expressed on keratinocytes and some dermal cells in lesional skin compared with very little expression on non-lesional skin and none on normal skin. (c) Toll-like receptor (TLR3) was strongly expressed on keratinocytes of lesional skin compared with a faint expression on normal and non-lesional skin. Scale bar=100 μm.