Meta-analysis of RNA sequencing data from 534 skin samples shows substantial IL-17 effects in non-lesional psoriatic skin

Psoriasis is a common chronic inflammatory skin disease characterized by disturbed interactions between infiltrating immune cells and keratinocytes. To enhance our understanding of the underlying molecular and cellular mechanisms driving psoriasis pathobiology, and to identify potential biomarkers for disease severity, we conducted RNA sequencing of skin biopsies from 75 patients with psoriasis vulgaris and 46 non-psoriatic controls. To increase the robustness of the results, we meta-analysed our data with four publicly available datasets, bringing the total number of samples to 534. By comparing lesional psoriatic (PP) to healthy control (NN) skin, we identified 2269 differentially expressed genes (DEGs) (|log2FC|>1.0, FDR <0.1), and 58 DEGs when comparing non-lesional psoriatic (PN) to NN skin. We also identified 54 DEGs associated with disease severity (PASI ≥ 10 vs. PASI <10). Cellular deconvolution analysis showed that differentiated keratinocytes emerged as the most prominent cell type among the DEGs in PP/NN. Functional enrichment analysis in PN/NN revealed several IL-17 related pathways and confirmed a previously reported "pre-inflammatory signature" across all psoriatic skin. This study provides insights into the psoriasis transcriptome and identifies a severity-specific signature, which may serve as candidate for future studies aimed at identifying psoriasis biomarkers and predicting disease progression. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We are grateful to all the volunteers who contributed to our study as well as to assistance from staff at the Clinical Research Facility, St. Olavs hospital, Trondheim University Hospital, Norway, Biobank1, Trondheim, Norway, the Clinical Research Unit, University Hospital of North Norway, Norway, the Research Biobank, University Hospital of North Norway, Norway and the Tromsø Study, UiT The Arctic University of Norway, Norway. The total RNA extraction, library preparation and RNA sequencing were performed in close collaboration with the Genomics Core Facility (GCF), at the Norwegian University of Science and Technology, NTNU, Trondheim, Norway. The GCF is funded by the Faculty of Medicine and Health Sciences at NTNU and Central Norway Regional Health Authority. All analyses were performed using digital laboratories in HUNT Cloud at the Norwegian University of Science and Technology, NTNU, Trondheim, Norway. We are grateful for outstanding support from the HUNT Cloud community. This work was supported by the Liaison Committee for Education, Research and Innovation in Central Norway (Grant number: 90154700) and the Joint Research Committee between St. Olavs hospital and the Faculty of Medicine and Health Sciences, NTNU (Grant numbers: 46055600-101 and 90053000). ML, PS, KH, KC, and LCO and SAH work in a research unit funded by Stiftelsen Kristian Gerhard Jebsen (Grant number: SKGJ-MED-015); Faculty of Medicine and Health Sciences, NTNU; The Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St. Olavs hospital and the Faculty of Medicine and Health Sciences, NTNU. ML was supported by a research grant from the Liaison Committee for education, research and innovation in Central Norway. Marita Jenssen, Kjersti Danielsen and Anne-Sofie Furberg were supported by grants from the Northern Norway Regional Health Authority (grant number HNF1361-17 [MJ] and SFP1167-14 [KD, ASF]), the Odd Berg Medical Research Foundation (MJ, KD) and the Norwegian Society of Dermatology and Venereology (MJ). The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants had provided written informed consent. The study was approved by the Regional Committee for Medical and Health Research Ethics in Mid-Norway (2016/281) and North-Norway (2016/789) and adheres to the Declaration of Helsinki Principles. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The normalized count matrix of 22 530 expressed genes from the local dataset is available from the corresponding authors upon reasonable request. Upon publication, count data will be deposited at NCBI GEO.