{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T12:51:06Z","timestamp":1770814266497,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Acquired cholesteatoma is a chronic inflammatory middle ear disease characterized by keratinizing squamous epithelium overgrowth and bone erosion. While the upregulation of pattern-recognition receptor (PRR) signaling has been consistently observed, it remains unclear whether this reflects a secondary response to microbial infection or a primary dysfunction driven by genetic predisposition. Methods: Using the UK Biobank, we analyzed 678 individuals with cholesteatoma (ICD-10: H71) among 502,164 participants. Candidate genes implicated in cholesteatoma-related inflammatory pathways (n = 17) were selected, and 147 polymorphisms were studied. Gene-specific genetic risk scores (GRSs) were calculated for cholesteatoma patients (GRSchol) and the general UK Biobank population (GRSpop). The difference (\u0394GRSchol-GRSpop) was used to assess the relative contribution of each gene. Results: Genes with the highest \u0394GRS were IL6, TREM1, IL1R1, IL1A, HIF1A, ID1, RAGE, and TNFA. These genes represent key downstream mediators and amplifiers of PRR signaling rather than the receptors themselves. Variants in cytokine genes (IL6, IL1R1, IL1A, and TNFA) may enhance inflammatory signaling and bone resorption; Trem1 amplifies TLR responses; RAGE sustains sterile DAMP-driven inflammation, while HIF1A and ID1 implicate hypoxia, tissue remodeling, and keratinocyte proliferation in disease persistence. Conclusions: Our findings suggest that cholesteatoma pathogenesis may not be driven solely by microbial activation of PRRs but rather by genetic variants that amplify and sustain downstream inflammatory responses. This supports a model of cholesteatoma as a disease of self-perpetuating inflammation triggered by diverse stressors, including microbial and non-microbial insults. These insights may inform preventive strategies targeting environmental stressors, as well as therapeutic approaches using biologics to interrupt chronic inflammatory amplification in cholesteatoma.<\/jats:p>","DOI":"10.3390\/jpm16020094","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:13:01Z","timestamp":1770289981000},"page":"94","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A UK Biobank Study on Genetic Variants in Pattern-Recognition Receptor (PRR) Signaling Indicates Self-Perpetuatin Inflammation of Cholesteatoma"],"prefix":"10.3390","volume":"16","author":[{"given":"Mohannad","family":"Almomani","sequence":"first","affiliation":[{"name":"Evangelismos General Hospital, Ipsilantou 45-47, 10676 Athens, Greece"},{"name":"Department of Otolaryngology-Head and Neck Surgery, Medical School, University of Thessaly, 3 Panepistimiou Str., 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2741-5877","authenticated-orcid":false,"given":"Ioannis","family":"Vlastos","sequence":"additional","affiliation":[{"name":"Evangelismos General Hospital, Ipsilantou 45-47, 10676 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalliopi","family":"Gkouskou","sequence":"additional","affiliation":[{"name":"Evangelismos General Hospital, Ipsilantou 45-47, 10676 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaos","family":"Drimalas","sequence":"additional","affiliation":[{"name":"Evangelismos General Hospital, Ipsilantou 45-47, 10676 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2312-7218","authenticated-orcid":false,"given":"Jiannis","family":"Hajiioannou","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology-Head and Neck Surgery, Medical School, University of Thessaly, 3 Panepistimiou Str., 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"d1088","DOI":"10.1136\/bmj.d1088","article-title":"Cholesteatoma","volume":"342","author":"Bhutta","year":"2011","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.otc.2024.07.022","article-title":"The Science of Cholesteatoma","volume":"58","author":"Patel","year":"2025","journal-title":"Otolaryngol. 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