Identification of key miRNAs and target genes in psoriasis vulgaris and obesity co-morbidity.

backgroundPsoriasis is a chronic inflammatory dermatological disorder, with psoriasis vulgaris (PA) being the most prevalent form. Obesity is a comorbid condition and a risk factor for psoriasis, sharing common susceptibility genes and inflammatory pathways. MicroRNAs (miRNAs) play a pivotal role in the pathogenesis of psoriasis. Exosomes, nanoscale extracellular vesicles, facilitate the stable intercellular transfer of miRNAs, reflecting their cellular origin, which makes them promising biomarkers for various diseases. Although much of the research on psoriasis has focused on tissue miRNAs, the role of exosomal miRNAs remains poorly understood. Notably, exosomal miRNAs regulate metabolic phenotypes, such as promoting insulin resistance in obesity. In psoriasis patients, plasma exosomal miRNAs have been shown to influence immune responses through metabolic reprogramming. These findings suggest that plasma exosomal miRNAs could serve as a mechanistic link between psoriasis and obesity.

methodsSix PA patients, six psoriasis vulgaris with obesity (PAO) patients, and six healthy controls (HC) were recruited. Plasma was centrifuged to isolate exosomes, which were characterized by transmission electron microscopy (TEM) for morphology, nanoparticle tracking analysis (NTA) for size distribution, and Western blotting (WB) for exosomal marker proteins. Plasma exosomal RNA was extracted and analyzed using next-generation sequencing (NGS) to profile miRNA expression. Least Absolute Shrinkage and Selection Operator (LASSO) regression was employed to identify key miRNAs associated with the psoriasis-obesity comorbidity. Target genes for these miRNAs were identified using miRecords ( http://c1.accurascience.com/miRecords ), miRTarBase ( https://mirtarbase.cuhk.edu.cn ), and TarBase ( https://bio.tools/tarbase# !). Functional enrichment analysis of the predicted target genes was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Summary-data-based Mendelian randomization (SMR) analysis was applied to the Genome-Wide Association Study (GWAS) dataset for obesity and psoriasis from the UK Biobank ( https://www.ukbiobank.ac.uk ) to identify genes significantly associated with both conditions. Finally, the key miRNA target genes were cross-referenced with the significant genes for psoriasis and obesity identified through SMR to pinpoint the most crucial target genes.

resultsA total of 214 differentially expressed plasma exosomal miRNAs were identified. Compared to the HC group, the PA group showed 27 up-regulated and 50 down-regulated miRNAs, while the PAO group exhibited 119 up-regulated and 31 down-regulated miRNAs. Thirty-four miRNAs were differentially expressed in both the PA and PAO groups compared to the HC group, with 19 up-regulated and 15 down-regulated. LASSO regression identified miR-20a-5p as a key miRNA associated with the psoriasis-obesity comorbidity. GO and KEGG pathway enrichment analyses indicated that the target genes of miR-20a-5p were primarily enriched in signaling pathways, including TNF, TGF-β, p53, and phosphoinositide pathways. SMR analysis identified CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase (CDIPT) as a target gene of miR-20a-5p, specifically within the phosphatidylinositol signaling pathway.

conclusionsmiR-20a-5p may contribute to the comorbidity of PA and obesity by targeting CDIPT and modulating the phosphatidylinositol (PtdIns) signaling pathway.