The molecular basis of systemic associations in psoriasis

The molecular basis of systemic associations in psoriasis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The molecular basis of systemic associations in psoriasis Manahel Mahmood Alsabbagh, Safa Taha, Moiz Bakhiet This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6280023/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Mar, 2025 Read the published version in Archives of Dermatological Research → Version 1 posted You are reading this latest preprint version Abstract Psoriasis is an inflammatory disease with systemic associations, many of which have unclear molecular bases. The aim of this study is to investigate the upregulated pathways in psoriasis. We conducted microarray reactions on blood-extracted RNA from two groups of patients: those with psoriasis and metabolic syndrome (n=9) compared to those with psoriasis only (n=9). We identified 187 upregulated genes in psoriasis and metabolic syndrome compared to psoriasis only. Examined using Wikipathways, we have identified pathways and molecules involved in seven associations of psoriasis: malignancy, angiogenesis, keratinocyte senescence and hyperproliferation, the metabolic syndrome, increased cilia formation, circadian rhythm disturbance, and Alzheimer’s disease. We have then verified our results by comparing our psoriasis samples (n=18) with healthy controls (n=30) and described new pathways and molecules involved in four other associations: non-alcoholic fatty liver disease, end-stage renal disease arrhythmia, and pulmonary fibrosis. This report enhances our understanding of each association and lays the groundwork to study these associations at a genomic level. It also offers a great opportunity to employ these genes for prognostic measures and to develop personalized and targeted treatments. Dermatology Adipogenesis Alzheimer’s disease Angiogenesis Arrhythmia Cancer Ciliary landscape Circadian rhythm EGF/EGFR signaling End-stage renal disease Endothelin Keratinocyte hyperproliferation Malignancy Metabolic syndrome Non-alcoholic fatty liver disease PI3K-AKT signaling Psoriasis Pulmonary fibrosis Ras signaling VEGFA-VEGFR2 signaling Figures Figure 1 1. Introduction Psoriasis is an inflammatory disease with systemic associations, many of which have unclear molecular bases. The aim of this study is to investigate the upregulated pathways in psoriasis, correlating them with systemic associations and briefly presenting relevant clinical implications. 2. Materials and Methods This study has been approved by the Research and Ethics Committee at the Arabian Gulf University (Reference E005-PI-04/17) and the Research Technical Support Team at the Ministry of Health (Reference FA/SA/518/2017). Full details about the materials and methods can be found elsewhere. 1 In summary, we conducted microarray reactions on blood-extracted RNA from two groups of patients: those with psoriasis and metabolic syndrome (n = 9) compared to those with psoriasis only (n = 9). Initially, we used psoriasis as a control group to mitigate unspecific background noise caused by inflammation. Therefore, we propose that the reported genes/pathways are differentially upregulated with clinical relevance. We have validated this upregulation in comparison to healthy controls at a later stage. 3. Results and discussion We identified 187 upregulated genes at p < 0.05, FDR < 0.05, and fold change ≥ 2 in patients with psoriasis and metabolic syndrome compared to psoriasis only, as shown in Supplementary Material 1. We first visualized the interaction between these genes using Reactome ( https://reactome.org/ ), Fig. 1 a. Then, we examined the 187 genes through WikiPathways (Transcriptome Analysis Console 4.0.1.36). We identified 12 upregulated pathways significant at > 1.3 (equivalent to p 3, Supplementary Material 2. We have correlated ten of these pathways with seven associations of psoriasis as follows: Malignancy : Psoriasis is associated with an increased risk of malignancy, including lymphoma, leukemia, and malignancies of the upper aerodigestive tract, pancreas, liver, and digestive tract. 2 We have identified four pathways in psoriasis that correlate with the increased risk of malignancy: cancer pathways (genes = 11, p = 0.0186), VEGFA - VEGFR2 signaling (genes = 8, p = 0.0069), PI3K - AKT signaling (genes = 8, p = 0.0209), and Ras signaling (genes = 4, p = 0.0295), highlighting the genes involved in liver cancer cell proliferation and metastasis ( PRRC2C ), genes that inhibit autophagy and promotes cancer progression ( TPR ), genes involved in resistance to chemotherapy ( MCL1) , and genes that are overexpressed in many other tumors ( RPS11 , SP1 , and RAC1 ). Angiogenesis : We have identified eight overexpressed genes ( PGK1 , PRKCB , RPL27 , TXN , PRRC2C , RPS11 , SOD2 , and RAC1 ) involved in the VEGFA - VEGFR2 signaling pathway including the promotion and regulation of endothelial cell proliferation. Among these upregulated genes, previous studies have shown that PRKCB promotes VEGFA-induced endothelial cell proliferation 3 and TXN promotes angiogenesis. 4 The activation of the VEGFA-VEGFR2 signaling pathway explains the pathognomonic Auspitz sign observed in clinical practice, as well as the dilated tortuous blood vessels seen in histological sections. This also supports the idea of targeting vascular endothelial growth factor A for psoriasis treatment. 5 Keratinocyte senescence and hyperproliferation : Five genes in the EGF / EGFR signaling pathway were upregulated two to three-fold with a p = 0.0036, explaining keratinocyte hyperstimulation and hyperproliferation. 6 In addition, four genes were upregulated two to 3.5 folds in the Ras signaling pathway (p = 0.0295), explaining the keratinocyte senescence-like features seen in the upper psoriatic epidermis. 7 The metabolic syndrome : There is a dose-response relationship between the severity of psoriasis and the development of metabolic syndrome reaching 98% in severe psoriasis. 8 Eight genes in the adipogenesis pathway (involved in obesity and adipocyte formation) and the endothelin pathway (involved in vasoconstriction, hypertension, atherosclerosis, and heart disease) were upregulated two-fold with p = 0.0095 and p = 0.0372, respectively. Among the upregulated genes, NRIP1 9 and SP1 10 are associated with obesity and white adipocyte formation. Increased cilia formation : Five genes ( RAB2A , MKLN1 (involved in ciliopathies), UBE2H , EIF5B , and RAC1 (required for ciliogenesis)) related to the ciliary landscape were overexpressed by two to four folds (p = 0.0115). Recent evidence suggests that IL-17 is associated with increased cilia formation in psoriatic keratinocytes, potentially affecting keratinocyte differentiation. 11 Circadian rhythm disturbance : Four genes related to circadian rhythm were upregulated two-fold (p = 0.0398) as follows: SFPQ (involved in the regulation of circadian rhythm), NRIP1 (involved in the circadian regulation of gene expression), DHX9 , and SETX (inhibits termination of circadian target genes). This helps to explain reports of patients with psoriasis experiencing significant circadian rhythm disruptions manifesting as changes in the circadian oscillation of heart rate and blood pressure as well as peripheral clock pathology leading to cell cycle irregularities, keratinocyte hyperproliferation, insufficient apoptosis of keratinocytes, dysregulation of resident and migratory immunocytes, and modulation of angiogenesis. 12 Alzheimer’s disease : Psoriasis is associated with an increased risk of Alzheimer’s disease. 13 Our analysis revealed the upregulation of genes involved in neuroinflammation and glutamatergic signaling (p = 0.012023), highlighting the role of IL-6 in disease pathogenesis. We validated the upregulation of relevant pathways in our psoriasis patients (n = 18) compared to healthy controls (Gene Expression Omnibus, accession GSE55201, n = 30) and confirmed the upregulation of additional pathways of malignancy, Alzheimer’s disease, the metabolic syndrome, and angiogenesis, Supplementary Material 3. While our initial intention was to validate the existing data, we identified pathways explaining the molecular basis of correlations between psoriasis and four additional systemic associations (Supplementary Material 3): Non-alcoholic fatty liver disease : Psoriasis is associated with increased odds ratio of non-alcoholic fatty liver disease reaching 1.67. 14 The current analysis showed the involvement of 36 upregulated genes in the non-alcoholic fatty liver disease pathway (p = 0.016188). End-stage renal disease : Psoriasis is associated with an increased hazard ratio of end-stage renal disease reaching 1.58. 15 The current analysis revealed the involvement of 22 upregulated genes in the primary focal segmental glomerulosclerosis pathway (p = 0.003346). Arrhythmia : Psoriasis has an adjusted hazard ratio of arrhythmia reaching 1.34. 16 This analysis showed the involvement of 20 upregulated genes in the arrhythmogenic right ventricular cardiomyopathy pathway (p = 0.019612). Pulmonary fibrosis : Psoriasis is associated with higher odds of idiopathic pulmonary fibrosis. 17 Our analysis showed the involvement of 20 upregulated genes in the lung fibrosis pathway (p = 0.003346). We then conducted Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealing 108 pathways (Supplementary Material 4 and Fig. 1 b) and Gene Ontology annotation enrichment analysis (Supplementary Materials 5–7 and Figs. 1 c- 1 e) for the gene set listed in Supplementary Material 2 using the ShinyGO 0.81 tool ( https://bioinformatics.sdstate.edu/go/ ). In summary, we have described the molecular basis of 11 associations reported in psoriasis. This report enhances our understanding of each association and lays the groundwork to study these associations at a genomic level. It also offers a great opportunity to employ these genes for prognostic measures and to develop personalized and targeted treatments. Declarations Conflict of Interests: The authors declare that they have no conflict of interest. Author Contributions Conceptualization: Manahel Mahmood Alsabbagh, Safa Taha; Methodology: Manahel Mahmood Alsabbagh, Moiz Bakhiet, Safa Taha; Resources: Safa Taha; Investigation: Manahel Mahmood Alsabbagh, Safa Taha; Validation: Manahel Mahmood Alsabbagh, Safa Taha; Formal Analysis: Manahel Mahmood Alsabbagh, Safa Taha; Data Curation: Manahel Mahmood Alsabbagh; Visualization: Manahel Mahmood Alsabbagh; Writing—Original Draft: Manahel Mahmood Alsabbagh; Writing—Review & Editing: Manahel Mahmood Alsabbagh; Supervision: Moiz Bakhiet, Safa Taha; Project Administration: Moiz Bakhiet, Safa Taha; Funding Acquisition: Moiz Bakhiet, Safa Taha. Acknowledgments This work was funded by the Arabian Gulf University [Reference Number E005-PI-04/17]. The sponsor had no role in the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the article for publication. Data Availability: Data generated during analysis is available in Supplementary Materials 1–7. Raw data is available upon a justified request from the corresponding author. References Alsabbagh MM, Bakhiet M, Taha S (2023) Upregulation of REL and WSB1 in Patients WithPsoriasis and Metabolic Syndrome. Int J Dermatology Venereol 6(4):189–194. https://doi.org/10.1097/JD9.0000000000000309 Geller S, Xu H, Lebwohl M, Nardone B, Lacouture ME, Kheterpal M (2018) Malignancy Risk and Recurrence with Psoriasis and its Treatments: A Concise Update. Am J Clin Dermatol 19(3):363–375. https://doi.org/10.1007/s40257-017-0337-2 Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK (2009) Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription. J Biol Chem 284(13):8567–8581. https://doi.org/10.1074/jbc.M808719200 Dunn LL, Buckle AM, Cooke JP, Ng MK (2010) The emerging role of the thioredoxin system in angiogenesis. Arterioscler Thromb Vasc Biol 30(11):2089–2098. https://doi.org/10.1161/ATVBAHA.110.209643 Luengas-Martinez A, Hardman-Smart J, Paus R, Young HS (2020) Vascular endothelial growth factor-A as a promising therapeutic target for the management of psoriasis. Exp Dermatol 29(8):687–698. https://doi.org/10.1111/exd.14151 Wang S, Zhang Z, Peng H, Zeng K (2019) Recent advances on the roles of epidermal growth factor receptor in psoriasis. Am J Transl Res 11(2):520–528 Mercurio L, Bailey J, Glick AB, Dellambra E, Scarponi C, Pallotta S et al (2024) RAS-activated PI3K/AKT signaling sustains cellular senescence via P53/P21 axis in experimental models of psoriasis. J Dermatol Sci 115(1):21–32. https://doi.org/10.1016/j.jdermsci.2024.03.002 Wu JJ, Kavanaugh A, Lebwohl MG, Gniadecki R, Merola JF (2022) Psoriasis and metabolic syndrome: implications for the management and treatment of psoriasis. J Eur Acad Dermatol Venereol 36(6):797–806. https://doi.org/10.1111/jdv.18044 Rosell M, Jones MC, Parker MG (2011) Role of nuclear receptor corepressor RIP140 in metabolic syndrome. Biochim Biophys Acta 1812(8):919–928. https://doi.org/10.1016/j.bbadis.2010.12.016 Chen S, Li H, Zhang J, Jiang S, Zhang M, Xu Y et al (2017) Identification of Sp1 as a Transcription Activator to Regulate Fibroblast Growth Factor 21 Gene Expression. Biomed Res Int 2017:8402035. https://doi.org/10.1155/2017/8402035 Rizaldy D, Toriyama M, Kato H, Fukui R, Fujita F, Nakamura M et al (2021) Increase in primary cilia in the epidermis of patients with atopic dermatitis and psoriasis. Exp Dermatol 30(6):792–803. https://doi.org/10.1111/exd.14285 Luengas-Martinez A, Paus R, Iqbal M, Bailey L, Ray DW, Young HS (2022) Circadian rhythms in psoriasis and the potential of chronotherapy in psoriasis management. Exp Dermatol 31(11):1800–1809. https://doi.org/10.1111/exd.14649 Kim M, Park HE, Lee SH, Han K, Lee JH (2020) Increased risk of Alzheimer's disease in patients with psoriasis: a nationwide population-based cohort study. Sci Rep 10(1):6454. https://doi.org/10.1038/s41598-020-63550-2 Ruan Z, Lu T, Chen Y, Yuan M, Yu H, Liu R et al (2022) Association Between Psoriasis and Nonalcoholic Fatty Liver Disease Among Outpatient US Adults. JAMA Dermatol 158(7):745–753. https://doi.org/10.1001/jamadermatol.2022.1609 Lee E, Han JH, Bang CH, Yoo SA, Han KD, Kim HN et al (2019) Risk of End-Stage Renal Disease in Psoriatic Patients: Real-World Data from a Nationwide Population-Based Cohort Study. Sci Rep 9(1):16581. https://doi.org/10.1038/s41598-019-53017-4 Chiu HY, Chang WL, Huang WF, Wen YW, Tsai YW, Tsai TF (2015) Increased risk of arrhythmia in patients with psoriatic disease: A nationwide population-based matched cohort study. J Am Acad Dermatol 73(3):429–438. https://doi.org/10.1016/j.jaad.2015.06.023 Chen L, Wei Y, Hu M, Liu Y, Zheng X (2024) Psoriasis may increase the risk of idiopathic pulmonary fibrosis: a two-sample Mendelian randomization study. Respir Res 25(1):101. https://doi.org/10.1186/s12931-024-02721-5 Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryMaterials17.pdf Cite Share Download PDF Status: Published Journal Publication published 19 Mar, 2025 Read the published version in Archives of Dermatological Research → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6280023","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":432271065,"identity":"314e53bc-125a-4cd1-9e39-5996711c17c9","order_by":0,"name":"Manahel Mahmood Alsabbagh","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8013-760X","institution":"Arabian Gulf University","correspondingAuthor":true,"prefix":"","firstName":"Manahel","middleName":"Mahmood","lastName":"Alsabbagh","suffix":""},{"id":432271066,"identity":"eff0044f-7e15-403c-b6f9-c7de9c0ce367","order_by":1,"name":"Safa Taha","email":"","orcid":"","institution":"Arabian Gulf University","correspondingAuthor":false,"prefix":"","firstName":"Safa","middleName":"","lastName":"Taha","suffix":""},{"id":432271067,"identity":"db88334a-4e4f-4c25-9b07-5cf6b4ad32b5","order_by":2,"name":"Moiz Bakhiet","email":"","orcid":"","institution":"Arabian Gulf University","correspondingAuthor":false,"prefix":"","firstName":"Moiz","middleName":"","lastName":"Bakhiet","suffix":""}],"badges":[],"createdAt":"2025-03-21 19:45:33","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6280023/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6280023/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00403-025-04172-4","type":"published","date":"2025-03-20T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79259463,"identity":"8009bdf4-0256-4c4b-9a12-a47ba71fe450","added_by":"auto","created_at":"2025-03-26 09:20:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":775202,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalysis of differentially upregulated genes in psoriasis and metabolic syndrome compared to psoriasis only. (a) \u003c/strong\u003eReacfoam of 187 differentially upregulated genes analyzed based on pathway significance and captures the immune system, cellular response to stimuli, and metabolism of RNA and proteins. Upregulated genes involved in the top WikiPathways were further analyzed through \u003cstrong\u003e(b)\u003c/strong\u003e Kyoto Encyclopedia of Genes and Genomes enrichment capturing pathways involved in malignancy and metabolic syndrome; and Gene Ontology annotation enrichment for \u003cstrong\u003e(c)\u003c/strong\u003eBiological Process highlighting pathways involved in response to stimuli such as chemicals, organics, and stress, \u003cstrong\u003e(d)\u003c/strong\u003e Cellular Component, and \u003cstrong\u003e(e)\u003c/strong\u003e Molecular Function (the top 20 pathways, all FDR \u0026lt;0.05).\u003c/p\u003e","description":"","filename":"Figure16.png","url":"https://assets-eu.researchsquare.com/files/rs-6280023/v1/0975441948ba30d96871b3de.png"},{"id":82751705,"identity":"9784286f-7488-4794-bb69-e8f3452a118b","added_by":"auto","created_at":"2025-05-14 21:43:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1315307,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6280023/v1/b5bdb971-e7b8-461c-9558-dd3779eaab77.pdf"},{"id":79259467,"identity":"bd032108-edb8-4dc3-891b-57429a7e1a05","added_by":"auto","created_at":"2025-03-26 09:20:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1241756,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials17.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6280023/v1/d8fd042fcdd7366ef4cb50fc.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eThe molecular basis of systemic associations in psoriasis\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePsoriasis is an inflammatory disease with systemic associations, many of which have unclear molecular bases. The aim of this study is to investigate the upregulated pathways in psoriasis, correlating them with systemic associations and briefly presenting relevant clinical implications.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003eThis study has been approved by the Research and Ethics Committee at the Arabian Gulf University (Reference E005-PI-04/17) and the Research Technical Support Team at the Ministry of Health (Reference FA/SA/518/2017). Full details about the materials and methods can be found elsewhere.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e In summary, we conducted microarray reactions on blood-extracted RNA from two groups of patients: those with psoriasis and metabolic syndrome (n\u0026thinsp;=\u0026thinsp;9) compared to those with psoriasis only (n\u0026thinsp;=\u0026thinsp;9). Initially, we used psoriasis as a control group to mitigate unspecific background noise caused by inflammation. Therefore, we propose that the reported genes/pathways are differentially upregulated with clinical relevance. We have validated this upregulation in comparison to healthy controls at a later stage.\u003c/p\u003e"},{"header":"3. Results and discussion","content":"\u003cp\u003eWe identified 187 upregulated genes at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, FDR\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and fold change\u0026thinsp;\u0026ge;\u0026thinsp;2 in patients with psoriasis and metabolic syndrome compared to psoriasis only, as shown in Supplementary Material 1. We first visualized the interaction between these genes using Reactome (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://reactome.org/\u003c/span\u003e\u003cspan address=\"https://reactome.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea. Then, we examined the 187 genes through WikiPathways (Transcriptome Analysis Console 4.0.1.36). We identified 12 upregulated pathways significant at \u0026gt;\u0026thinsp;1.3 (equivalent to p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), and genes\u0026thinsp;\u0026gt;\u0026thinsp;3, Supplementary Material 2. We have correlated ten of these pathways with seven associations of psoriasis as follows:\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eMalignancy\u003c/b\u003e: Psoriasis is associated with an increased risk of malignancy, including lymphoma, leukemia, and malignancies of the upper aerodigestive tract, pancreas, liver, and digestive tract.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e We have identified four pathways in psoriasis that correlate with the increased risk of malignancy: cancer pathways (genes\u0026thinsp;=\u0026thinsp;11, p\u0026thinsp;=\u0026thinsp;0.0186), \u003cem\u003eVEGFA\u003c/em\u003e-\u003cem\u003eVEGFR2\u003c/em\u003e signaling (genes\u0026thinsp;=\u0026thinsp;8, p\u0026thinsp;=\u0026thinsp;0.0069), \u003cem\u003ePI3K\u003c/em\u003e-\u003cem\u003eAKT\u003c/em\u003e signaling (genes\u0026thinsp;=\u0026thinsp;8, p\u0026thinsp;=\u0026thinsp;0.0209), and Ras signaling (genes\u0026thinsp;=\u0026thinsp;4, p\u0026thinsp;=\u0026thinsp;0.0295), highlighting the genes involved in liver cancer cell proliferation and metastasis (\u003cem\u003ePRRC2C\u003c/em\u003e), genes that inhibit autophagy and promotes cancer progression (\u003cem\u003eTPR\u003c/em\u003e), genes involved in resistance to chemotherapy (\u003cem\u003eMCL1)\u003c/em\u003e, and genes that are overexpressed in many other tumors (\u003cem\u003eRPS11\u003c/em\u003e, \u003cem\u003eSP1\u003c/em\u003e, and \u003cem\u003eRAC1\u003c/em\u003e).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eAngiogenesis\u003c/b\u003e: We have identified eight overexpressed genes (\u003cem\u003ePGK1\u003c/em\u003e, \u003cem\u003ePRKCB\u003c/em\u003e, \u003cem\u003eRPL27\u003c/em\u003e, \u003cem\u003eTXN\u003c/em\u003e, \u003cem\u003ePRRC2C\u003c/em\u003e, \u003cem\u003eRPS11\u003c/em\u003e, \u003cem\u003eSOD2\u003c/em\u003e, and \u003cem\u003eRAC1\u003c/em\u003e) involved in the \u003cem\u003eVEGFA\u003c/em\u003e-\u003cem\u003eVEGFR2\u003c/em\u003e signaling pathway including the promotion and regulation of endothelial cell proliferation. Among these upregulated genes, previous studies have shown that \u003cem\u003ePRKCB\u003c/em\u003e promotes VEGFA-induced endothelial cell proliferation\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e and \u003cem\u003eTXN\u003c/em\u003e promotes angiogenesis.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e The activation of the \u003cem\u003eVEGFA-VEGFR2\u003c/em\u003e signaling pathway explains the pathognomonic Auspitz sign observed in clinical practice, as well as the dilated tortuous blood vessels seen in histological sections. This also supports the idea of targeting vascular endothelial growth factor A for psoriasis treatment.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eKeratinocyte senescence and hyperproliferation\u003c/b\u003e: Five genes in the \u003cem\u003eEGF\u003c/em\u003e/\u003cem\u003eEGFR\u003c/em\u003e signaling pathway were upregulated two to three-fold with a p\u0026thinsp;=\u0026thinsp;0.0036, explaining keratinocyte hyperstimulation and hyperproliferation.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e In addition, four genes were upregulated two to 3.5 folds in the Ras signaling pathway (p\u0026thinsp;=\u0026thinsp;0.0295), explaining the keratinocyte senescence-like features seen in the upper psoriatic epidermis.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eThe metabolic syndrome\u003c/b\u003e: There is a dose-response relationship between the severity of psoriasis and the development of metabolic syndrome reaching 98% in severe psoriasis.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Eight genes in the adipogenesis pathway (involved in obesity and adipocyte formation) and the endothelin pathway (involved in vasoconstriction, hypertension, atherosclerosis, and heart disease) were upregulated two-fold with p\u0026thinsp;=\u0026thinsp;0.0095 and p\u0026thinsp;=\u0026thinsp;0.0372, respectively. Among the upregulated genes, \u003cem\u003eNRIP1\u003c/em\u003e\u003csup\u003e9\u003c/sup\u003e and \u003cem\u003eSP1\u003c/em\u003e\u003csup\u003e10\u003c/sup\u003e are associated with obesity and white adipocyte formation.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eIncreased cilia formation\u003c/b\u003e: Five genes (\u003cem\u003eRAB2A\u003c/em\u003e, \u003cem\u003eMKLN1\u003c/em\u003e (involved in ciliopathies), \u003cem\u003eUBE2H\u003c/em\u003e, \u003cem\u003eEIF5B\u003c/em\u003e, and \u003cem\u003eRAC1\u003c/em\u003e (required for ciliogenesis)) related to the ciliary landscape were overexpressed by two to four folds (p\u0026thinsp;=\u0026thinsp;0.0115). Recent evidence suggests that IL-17 is associated with increased cilia formation in psoriatic keratinocytes, potentially affecting keratinocyte differentiation.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eCircadian rhythm disturbance\u003c/b\u003e: Four genes related to circadian rhythm were upregulated two-fold (p\u0026thinsp;=\u0026thinsp;0.0398) as follows: \u003cem\u003eSFPQ\u003c/em\u003e (involved in the regulation of circadian rhythm), \u003cem\u003eNRIP1\u003c/em\u003e (involved in the circadian regulation of gene expression), \u003cem\u003eDHX9\u003c/em\u003e, and \u003cem\u003eSETX\u003c/em\u003e (inhibits termination of circadian target genes). This helps to explain reports of patients with psoriasis experiencing significant circadian rhythm disruptions manifesting as changes in the circadian oscillation of heart rate and blood pressure as well as peripheral clock pathology leading to cell cycle irregularities, keratinocyte hyperproliferation, insufficient apoptosis of keratinocytes, dysregulation of resident and migratory immunocytes, and modulation of angiogenesis.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eAlzheimer\u0026rsquo;s disease\u003c/b\u003e: Psoriasis is associated with an increased risk of Alzheimer\u0026rsquo;s disease.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Our analysis revealed the upregulation of genes involved in neuroinflammation and glutamatergic signaling (p\u0026thinsp;=\u0026thinsp;0.012023), highlighting the role of \u003cem\u003eIL-6\u003c/em\u003e in disease pathogenesis.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eWe validated the upregulation of relevant pathways in our psoriasis patients (n\u0026thinsp;=\u0026thinsp;18) compared to healthy controls (Gene Expression Omnibus, accession GSE55201, n\u0026thinsp;=\u0026thinsp;30) and confirmed the upregulation of additional pathways of malignancy, Alzheimer\u0026rsquo;s disease, the metabolic syndrome, and angiogenesis, Supplementary Material 3. While our initial intention was to validate the existing data, we identified pathways explaining the molecular basis of correlations between psoriasis and four additional systemic associations (Supplementary Material 3):\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eNon-alcoholic fatty liver disease\u003c/b\u003e: Psoriasis is associated with increased odds ratio of non-alcoholic fatty liver disease reaching 1.67.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e The current analysis showed the involvement of 36 upregulated genes in the non-alcoholic fatty liver disease pathway (p\u0026thinsp;=\u0026thinsp;0.016188).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eEnd-stage renal disease\u003c/b\u003e: Psoriasis is associated with an increased hazard ratio of end-stage renal disease reaching 1.58.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e The current analysis revealed the involvement of 22 upregulated genes in the primary focal segmental glomerulosclerosis pathway (p\u0026thinsp;=\u0026thinsp;0.003346).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003eArrhythmia\u003c/b\u003e: Psoriasis has an adjusted hazard ratio of arrhythmia reaching 1.34.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e This analysis showed the involvement of 20 upregulated genes in the arrhythmogenic right ventricular cardiomyopathy pathway (p\u0026thinsp;=\u0026thinsp;0.019612).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003ePulmonary fibrosis\u003c/b\u003e: Psoriasis is associated with higher odds of idiopathic pulmonary fibrosis.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Our analysis showed the involvement of 20 upregulated genes in the lung fibrosis pathway (p\u0026thinsp;=\u0026thinsp;0.003346).\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eWe then conducted Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealing 108 pathways (Supplementary Material 4 and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb) and Gene Ontology annotation enrichment analysis (Supplementary Materials 5\u0026ndash;7 and Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec-\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee) for the gene set listed in Supplementary Material 2 using the ShinyGO 0.81 tool (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://bioinformatics.sdstate.edu/go/\u003c/span\u003e\u003cspan address=\"https://bioinformatics.sdstate.edu/go/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn summary, we have described the molecular basis of 11 associations reported in psoriasis. This report enhances our understanding of each association and lays the groundwork to study these associations at a genomic level. It also offers a great opportunity to employ these genes for prognostic measures and to develop personalized and targeted treatments.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eConflict of Interests:\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e \u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eConceptualization: Manahel Mahmood Alsabbagh, Safa Taha; Methodology: Manahel Mahmood Alsabbagh, Moiz Bakhiet, Safa Taha; Resources: Safa Taha; Investigation: Manahel Mahmood Alsabbagh, Safa Taha; Validation: Manahel Mahmood Alsabbagh, Safa Taha; Formal Analysis: Manahel Mahmood Alsabbagh, Safa Taha; Data Curation: Manahel Mahmood Alsabbagh; Visualization: Manahel Mahmood Alsabbagh; Writing\u0026mdash;Original Draft: Manahel Mahmood Alsabbagh; Writing\u0026mdash;Review \u0026amp; Editing: Manahel Mahmood Alsabbagh; Supervision: Moiz Bakhiet, Safa Taha; Project Administration: Moiz Bakhiet, Safa Taha; Funding Acquisition: Moiz Bakhiet, Safa Taha.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eThis work was funded by the Arabian Gulf University [Reference Number E005-PI-04/17]. The sponsor had no role in the study design; the collection, analysis, or interpretation of data; the writing of the report; or the decision to submit the article for publication.\u003c/p\u003e\u003ch2\u003eData Availability:\u003c/h2\u003e \u003cp\u003eData generated during analysis is available in Supplementary Materials 1\u0026ndash;7. Raw data is available upon a justified request from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlsabbagh MM, Bakhiet M, Taha S (2023) Upregulation of REL and WSB1 in Patients WithPsoriasis and Metabolic Syndrome. 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Respir Res 25(1):101. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12931-024-02721-5\u003c/span\u003e\u003cspan address=\"10.1186/s12931-024-02721-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"10bf5b2a-1082-4ab7-859d-4be7b5222332","identifier":"10.13039/100009606","name":"Arabian Gulf University","awardNumber":"E005-PI-04/17","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"Arabian Gulf University","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adipogenesis, Alzheimer’s disease, Angiogenesis, Arrhythmia, Cancer, Ciliary landscape, Circadian rhythm, EGF/EGFR signaling, End-stage renal disease, Endothelin, Keratinocyte hyperproliferation, Malignancy, Metabolic syndrome, Non-alcoholic fatty liver disease, PI3K-AKT signaling, Psoriasis, Pulmonary fibrosis, Ras signaling, VEGFA-VEGFR2 signaling","lastPublishedDoi":"10.21203/rs.3.rs-6280023/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6280023/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePsoriasis is an inflammatory disease with systemic associations, many of which have unclear molecular bases. The aim of this study is to investigate the upregulated pathways in psoriasis. We conducted microarray reactions on blood-extracted RNA from two groups of patients: those with psoriasis and metabolic syndrome (n=9) compared to those with psoriasis only (n=9). We identified 187 upregulated genes in psoriasis and metabolic syndrome compared to psoriasis only. Examined using Wikipathways, we have identified pathways and molecules involved in seven associations of psoriasis: malignancy, angiogenesis, keratinocyte senescence and hyperproliferation, the metabolic syndrome, increased cilia formation, circadian rhythm disturbance, and Alzheimer’s disease. We have then verified our results by comparing our psoriasis samples (n=18) with healthy controls (n=30) and described new pathways and molecules involved in four other associations: non-alcoholic fatty liver disease, end-stage renal disease arrhythmia, and pulmonary fibrosis. This report enhances our understanding of each association and lays the groundwork to study these associations at a genomic level. It also offers a great opportunity to employ these genes for prognostic measures and to develop personalized and targeted treatments.\u003c/p\u003e","manuscriptTitle":"The molecular basis of systemic associations in psoriasis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-26 09:20:34","doi":"10.21203/rs.3.rs-6280023/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5a7935a5-6475-44d9-8452-0f08ae733d32","owner":[],"postedDate":"March 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46045583,"name":"Dermatology"}],"tags":[],"updatedAt":"2025-05-14T21:43:02+00:00","versionOfRecord":{"articleIdentity":"rs-6280023","link":"https://doi.org/10.1007/s00403-025-04172-4","journal":{"identity":"archives-of-dermatological-research","isVorOnly":false,"title":"Archives of Dermatological Research"},"publishedOn":"2025-03-20 00:00:00","publishedOnDateReadable":"March 20th, 2025"},"versionCreatedAt":"2025-03-26 09:20:34","video":"","vorDoi":"10.1007/s00403-025-04172-4","vorDoiUrl":"https://doi.org/10.1007/s00403-025-04172-4","workflowStages":[]},"version":"v1","identity":"rs-6280023","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6280023","identity":"rs-6280023","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}