Background Aberrant DNA methylation patterns are of increasing interest in the study of psoriasis mechanisms. This study aims to screen potential diagnostic indicators affected by DNA methylation for psoriasis based on bioinformatics using multiple machine learning algorithms and to preliminarily explore its molecular mechanisms. Methods GSE13355, GSE14905, and GSE73894 were collected from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated region- (DMR-) genes between psoriasis and control samples were combined to obtain differentially expressed methylated genes. Subsequently, a protein-protein interaction (PPI) network was established to analyze the interaction between differentially expressed methylated genes. Moreover, the hub genes of psoriasis were screened by the least absolute shrinkage and selection operator (LASSO), Random Forest (RF), and Support Vector Machine (SVM), which were further performed single-gene gene set enrichment analysis (GSEA) to clarify the pathogenesis of psoriasis. The druggable genes were predicted using DGIdb. Finally, the expressions of hub genes in psoriasis lesions and healthy controls were detected by immunohistochemistry (IHC) and quantitative real-time PCR (RT-qPCR). Results In this study, a total of 767 DEGs and 896 DMR-genes were obtained. Functional enrichment showed that they were significantly associated with skin development, skin barrier function, immune/inflammatory response, and cell cycle. The combined transcriptomic and DNA methylation data resulted in 33 differentially expressed methylated genes, of which GJB2 was the final identified hub gene for psoriasis, with robust diagnostic power. IHC and RT-qPCR showed that GJB2 was significantly higher in psoriasis samples than those in healthy controls. Additionally, GJB2 may be involved in the development and progression of psoriasis by disrupting the body's immune system, mediating the cell cycle, and destroying the skin barrier, in addition to possibly inducing diseases related to the skeletal aspects of psoriasis. Moreover, OCTANOL and CARBENOXOLONE were identified as promising compounds through the DGIdb database. Conclusion The abnormal expression of GJB2 might play a critical role in psoriasis development and progression. The genes identified in our study might serve as a diagnostic indicator and therapeutic target in psoriasis.

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Exploration of Biomarkers of Psoriasis through Combined Multiomics Analysis

Background The human major histocompatibility complex (MHC) is known to be highly polymorphic and has been identified to be associated with numerous diseases. The HLA-DPB1 and BTNL2 genes were associated with psoriasis for the first time. The present study aims to investigate the relevance of the HLA-DPB1 and BTNL2 genes with respect to clinical phenotypes of psoriasis vulgaris (PV). Methods To investigate whether the HLA-DPB1 and BTNL2 polymorphisms were associated with clinical phenotypes of PV in Chinese Han population, we conducted an analysis in case-controls and case-only subjects (9906 controls and 8744 cases) via MHC targeted sequencing stratified analysis. Results In cases and controls, analysis showed that the genotype of HLA-DPB1*05:01 was associated with type of guttate [p = 3.914 × 10-2 , odds ratio (OR = 0.9335)] and northern region (p = 1.182 × 10-3 , OR = 0.9108). In the case-only analysis, the genotype of HLA-DPB1*05:01 was significantly correlated with geographical region (p = 1.36 × 10-3 , OR = 1.134). In cases and controls, analysis showed that the genotype of BTNL2 (rs 41355746) was associated with being male (p = 2.563 × 10-2 , OR = 0.8897), early-onset (p = 9.399 × 10-3 , OR = 0.8856), guttate (p = 2.469 × 10-2 , OR = 0.8558) and family history (p = 1.51 × 10-4 , OR = 0.772). In the case-only analysis, the genotype of BTNL2 (rs41355746) was significantly correlated with family history (p = 1.768 × 10-3 , OR = 0.757) and age of onset (p = 3.818 × 10-2 , OR = 1.195). Conclusions The results of the present study indicate that the HLA-DPB1*05:01 gene was associated with the geographical region of PV and the BTNL2 gene was significantly associated with family history and age of onset of PV. In conclusion, the HLA-DPB1*05:01 and BTNL2 genes might be responsible for the complicacy of clinical features.

Correlation analysis of the HLA-DPB1*05:01 and BTNL2 genes within the histocompatibility complex region with a clinical phenotype of psoriasis vulgaris in the Chinese Han population.

Abstract Background : Aberrant DNA methylation patterns are of increasing interest in the study of psoriasis mechanisms. This study aims to screen potential diagnostic indicators affected by DNA methylation for psoriasis based on bioinformatics using multiple machine learning algorithms and to preliminarily explore its molecular mechanisms. Methods : GSE13355, GSE14905, and GSE73894 were collected from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) and differentially methylated region (DMR)-genes between psoriasis and control samples were combined to obtain differentially expressed methylated genes. Subsequently, protein-protein interaction (PPI) network establishment, multiple machine learning algorithm analysis, including, the least absolute shrinkage and selection operator (LASSO), Random Forest (RF), and Support Vector Machine (SVM), receiver operating characteristic (ROC) curve analysis, and single-gene gene set enrichment analysis (GSEA) were performed to analyze the interaction networks, to recognize hub genes, and to clarify the pathogenesis of psoriasis. The druggable genes were predicted using DGIdb. The expression of GJB2 in psoriasis lesions and healthy controls was detected by immunohistochemistry (IHC) and quantitative real-time PCR(RT-qPCR). Results: In this study, a total of 767 DEGs and 896 DMR-genes were obtained. Functional enrichment showed that they were significantly associated with skin development, skin barrier function, immune/inflammatory response, and cell cycle. The combined transcriptomic and DNA methylation data resulted in 33 differentially expressed methylated genes, of which The gap junction beta 2 (GJB2) was the final identified hub gene for psoriasis, with the robust diagnostic power. IHC and RT-qPCR showed that GJB2 was significant higher in psoriasis than that in healthy controls. Single gene GSEA suggested that GJB2 may be involved in the development and progression of psoriasis by disrupting the body's immune system, mediating the cell cycle, and destroying the skin barrier, in addition to possibly inducing diseases related to the skeletal aspects of psoriasis. Moreover, OCTANOL and CARBENOXOLONE were identified as promising compounds through the DGIdb database. Conclusion: Our findings suggest that the abnormal expression of GJB2 may play a critical role in psoriasis development and progression. The genes identified in our study may serve as a diagnostic indicator and therapeutic target in psoriasis. 

Exploration of biomarkers of psoriasis through combined multiomics analysis

The epidermis, the outermost layer of the skin, serves as a protective barrier against external factors. Epidermal differentiation, a tightly regulated process essential for epidermal homeostasis, epidermal barrier formation and skin integrity maintenance, is orchestrated by several players, including signaling molecules, calcium gradient and junctional complexes such as gap junctions (GJs). GJ proteins, known as connexins facilitate cell-to-cell communication between adjacent keratinocytes. Connexins can function as either hemichannels or GJs, depending on their interaction with other connexons from neighboring keratinocytes. These channels enable the transport of metabolites, cAMP, microRNAs, and ions, including Ca2+, across cell membranes. At least ten distinct connexins are expressed within the epidermis and mutations in at least five of them has been linked to various skin disorders. Connexin mutations may cause aberrant channel activity by altering their synthesis, their gating properties, their intracellular trafficking, and the assembly of hemichannels and GJ channels. In addition to mutations, connexin expression is dysregulated in other skin conditions including psoriasis, chronic wound and skin cancers, indicating the crucial role of connexins in skin homeostasis. Current treatment options for conditions with mutant or altered connexins are limited and primarily focus on symptom management. Several therapeutics, including non-peptide chemicals, antibodies, mimetic peptides and allele-specific small interfering RNAs are promising in treating connexin-related skin disorders. Since connexins play crucial roles in maintaining epidermal homeostasis as shown with linkage to a range of skin disorders and cancer, further investigations are warranted to decipher the molecular and cellular alterations within cells due to mutations or altered expression, leading to abnormal proliferation and differentiation. This would also help characterize the roles of each isoform in skin homeostasis, in addition to the development of innovative therapeutic interventions. This review highlights the critical functions of connexins in the epidermis and the association between connexins and skin disorders, and discusses potential therapeutic options.

Connexins in epidermal health and diseases: insights into their mutations, implications, and therapeutic solutions

Psoriasis is a chronic multifactorial disease and is considered to be strongly associated with the major histocompatibility complex (MHC) region. We have discovered an independent, novel and susceptible psoriasis risk HLA loci, rs9266150; P = 4.52 × 10-9 for the first time. In this study, we aimed to verify the relationship between the susceptible locus and the subphenotypes of psoriasis vulgaris (PV), including geographic location, gender, age of onset, family history and present skin lesion types (chronic plaque and guttate). To investigate the distribution and association of the rs9266150 gene with clinical phenotypes of PV in Chinese Han population, we conducted an analysis in case-control and case-only subjects in the 9906 controls and 8744 cases by MHC targeted sequencing stratified analysis in this study. Significant associations were found with a northern geographic location in the case-only (P = 1.97 × 10-4 ) and the subphenotype-control analyses (P = 5.57 × 10-5 ), males in the case-only (P = 4.77 × 10-3 ) and the subphenotype-control analyses (P = 7.31 × 10-4 ), and guttate psoriasis in the case-only (P = 4.08 × 10-3 ) and the subphenotype-control analyses (P = 1.27 × 10-3 ). There were no significant differences observed between the age of onset (OR = 1.062, 95% CI: 0.9725-1.16, P = 1.8 × 10-1 ) and the family history of psoriasis (OR = 0.981, 95% CI: 0.9048-1.064, P = 6.43 × 10-1 ). The recessive model provided the best fit for rs9266150 (P = 4.38 × 10-7 ). Our results implied that rs9266150 might not only play an important role in the development of psoriasis, but also be positively associated with the geographic location, gender and present skin lesion in the Chinese population.

Association of the novel susceptible locus rs9266150 with clinical features of psoriasis vulgaris in the Chinese Han population.

Our recent targeted sequencing study identified a missense single-nucleotide polymorphism rs72474224 (c.324C>T) in GJB2. To investigate the correlation between rs72474224 (c.324C>T) and subphenotypes of psoriasis, genotype data for rs72474224 (c.324C>T, p.Val37Ile) was analyzed in 9946 cases and 9906 controls. The additive model provided the best fit for rs72474224 (P = 7.34 × 10(-9)). The genotypic and allelic frequency distributions were associated with plaque psoriasis in case-only (Pgenotype = 2.67 × 10(-3), Pallele = 6.22 × 10(-4)) and subphenotype-control (Pgenotype = 1.58 × 10(-11), Pallele = 8.16 × 10(-12)) analyses. No other significant difference was found in case-only analyses. Rs72474224 in GJB2 is preferentially associated with plaque psoriasis in Chinese population and might contribute to the complexity of psoriasis clinical features.

A genetic coding variant rs72474224 in GJB2 is associated with clinical features of psoriasis vulgaris in a Chinese Han population

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A genetic coding variant rs72474224 in GJB2 is associated with clinical features of psoriasis vulgaris in a Chinese Han population