{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T12:16:16Z","timestamp":1783340176557,"version":"3.54.6"},"reference-count":68,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Arthritis","award":["K23AR077073"],"award-info":[{"award-number":["K23AR077073"]}]},{"DOI":"10.13039\/100000002","name":"Musculoskeletal and Skin Diseases of the National Institutes of Health","doi-asserted-by":"publisher","award":["K23AR077073"],"award-info":[{"award-number":["K23AR077073"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p &lt; 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p &lt; 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin\u2013liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.<\/jats:p>","DOI":"10.3390\/genes15020146","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T07:22:32Z","timestamp":1705994552000},"page":"146","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dysregulation of the Skin\u2013Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis"],"prefix":"10.3390","volume":"15","author":[{"given":"Melika","family":"Marani","sequence":"first","affiliation":[{"name":"Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vrinda","family":"Madan","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas K.","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwen","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin K.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Z.","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn G.","family":"Kwatra","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1056\/NEJMe1916733","article-title":"Breaking the Itch\u2013Scratch Cycle in Prurigo Nodularis","volume":"382","author":"Kwatra","year":"2020","journal-title":"N. 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