| dc.description.abstract | Introduction: Psoriasis is a common chronic inflammatory skin disease with a substantial genetic etiological component. It is associated with diverse comorbidities, increasing the disease burden. Estimated global prevalence is ~2%, but the prevalence in Norway has been estimated to be as high as 5.8%–11.4%. Knowledge gaps remain in our understanding of the etiology of psoriasis, and despite efforts to discover biomarkers for disease trajectories, much is still unknown.
Objectives: The overarching aim of this thesis was to investigate genomic alterations in psoriasis and their effects on psoriasis pathology and disease burden. Specifically, we established a psoriasis biobank for next-generation RNA-sequencing studies of coding and non-coding RNAs (messenger [mRNA], long non-coding [lncRNA], and micro [miRNA]; Papers I and II) and performed observational epidemiological investigations in a general population (Paper III).
Materials and methods: For transcriptional profiling of psoriasis (Papers I and II), we collected full-thickness skin biopsies from psoriatic cases (n = 75) and non-psoriatic controls (n = 46) at St. Olavs hospital, Trondheim and the University Hospital of North Norway, Tromsø. Both coding and non-coding RNAs (miRNA, mRNA, lncRNA) were sequenced, and differential gene expression analyses compared lesional skin (PP), nonlesional skin (PN), and control skin (NN). To identify severity-specific transcripts, we dichotomized cases into moderate/severe (Psoriasis Area and Severity Index [PASI] ≥10) and mild (PASI <10) and compared them in a differential gene expression analysis. Then, we meta-analyzed our data with publicly available datasets. We identified the potential biological functions of differentially expressed miRNAs (DEMs) and mRNAs (DEGs) via pathway analyses using various bioinformatic tools, including TargetScan, Kyoto Encyclopedia of Genes and Genomes, and QIAGEN Ingenuity Pathway Analysis. In Paper III, we conducted a population-based cross-sectional analysis using data from 56,042 individuals in the fourth wave of the Trøndelag Health Study (HUNT4). We assessed associations between psoriasis and body composition (measured using bioelectrical impedance analysis), cardiometabolic risk factors, and comorbidities.Furthermore, we investigated the associations between HLA-C*06:02 status, a potential biomarker for a distinct psoriasis endotype, and these outcomes.
Results: In Paper I, we identified 395 significant DEMs; (absolute log2 fold change [|log2FC|] > 0, false discovery rate [FDR] < 0.05) between PP and NN skin (PP/NN). We identified 20 DEMs between PN and NN skin (PN/NN). Notably, 85 of the identified DEMs had not previously been associated with psoriasis. We further found that 11 DEMs were related to disease severity in the Norwegian University of Science and Technology (NTNU) dataset. The predicted targets of the DEMs were enriched for terms that relate to comorbid diseases. In Paper II, the meta-analysis identified 2,269 DEGs in PP/NN and 58 DEGs in PN/NN (|log2FC| > 1.0, FDR < 0.1). In the NTNU dataset, 54 DEGs were related to disease severity. Pathway analysis identified enrichment of well-known inflammatory pathways in PP/NN. In PN/NN, many of the top most enriched pathways were related to IL-17 signaling, indicating that these effects are also relevant in macroscopically healthy skin and highlighting the systemic effects of psoriasis. In Paper III, the self-reported prevalence of psoriasis was found to be 6.6% in HUNT4. Psoriasis was associated with increased adiposity measures, including increased body and visceral fat, decreased skeletal muscle and soft lean mass, and higher prevalence of cardiovascular, respiratory, and endocrine disorders. Among HLA-C*06:02-positive individuals with psoriasis, high-sensitivity C-reactive protein (hsCRP) levels were lower, atrial fibrillation was more prevalent, and migraines were less prevalent compared to HLA-C*06:02-negative individuals.
Conclusion: We have provided a comprehensive overview of the psoriasis transcriptome in psoriatic skin and specifically identified DEMs and DEGs related to disease severity. We found a persistently high self-reported prevalence of psoriasis in a general population and provided additional evidence for increased comorbid burden in psoriasis. Our results have outlined potential directions for future studies of functional implications of the dysregulated transcriptome in psoriasis. Increased knowledge of the pathological mechanisms that drive psoriasis may aid in developing effective and safe therapeutic strategies and identifying biomarkers predicting various disease trajectories. | en_US |
