A UK Biobank Study on Genetic Variants in Pattern-Recognition Receptor (PRR) Signaling Indicates Self-Perpetuatin Inflammation of Cholesteatoma

<b>Background</b>: 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. <b>Methods</b>: 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 (ΔGRSchol-GRSpop) was used to assess the relative contribution of each gene. <b>Results</b>: Genes with the highest ΔGRS were <i>IL6</i>, <i>TREM1</i>, <i>IL1R1</i>, <i>IL1A</i>, <i>HIF1A</i>, <i>ID1</i>, <i>RAGE</i>, and <i>TNFA</i>. These genes represent key downstream mediators and amplifiers of PRR signaling rather than the receptors themselves. Variants in cytokine genes (<i>IL6</i>, <i>IL1R1</i>, <i>IL1A</i>, and <i>TNFA</i>) may enhance inflammatory signaling and bone resorption; <i>Trem1</i> amplifies TLR responses; <i>RAGE</i> sustains sterile DAMP-driven inflammation, while <i>HIF1A</i> and <i>ID1</i> implicate hypoxia, tissue remodeling, and keratinocyte proliferation in disease persistence. <b>Conclusions</b>: 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.