목적: Cisplatin-induced ototoxicity (CIO), causing permanent hearing loss in over 50% of treated cancer patients, has varying individual responses, suggesting genetic predispositions. We investigated genetic associations between CIO and Toll-like receptor 4 (TLR4), an immune receptor known to mediate inflammatory responses to cisplatin, and evaluated the functional impact of these variants on TLR4 expression. 방법:We conducted a case-control candidate gene study in 213 adult head and neck cancer patients and 357 pediatric oncology patients, all treated with cisplatin. Cases were defined as patients who developed grade 2 hearing lossCTCAE v4.0). Genetic associations were assessed using logistic regression adjusted for clinical factors. Significant associations were meta-analyzed across cohorts. Functional studies were performed in HeLa cells, measured TLR4 expression changes following cisplatin exposure and tested the impact of TLR4 variants on cisplatin- induced TLR4 transcription using luciferase reporter assays. 결과:Meta-analysis of both cohorts identified 20 TLR4 variants significantly associated with protection against CIO. The most significant association was rs16905901 (P=8.06E-07, OR=0.27, 95% CI: 0.17-0.43). Functional analysis revealed that cisplatin induces TLR4 expression in a dose- and time-dependent manner. Two promoter variants, rs10759932 and rs10116253, significantly reduced cisplatin-induced TLR4 promoter activity in cellular assays. The rs10759932 variant-containing promoter showed significantly decreased activity compared to wild-type following cisplatin treatment (P=0.005). 결론:This study provides the first evidence linking TLR4 genetic variants to protection against cisplatin-induced hearing loss in human patients. The identified variants appear to function by reducing cisplatin-induced TLR4 expression. These findings support previous mechanistic studies implicating TLR4 in CIO and suggest that TLR4 downregulation may protect against this adverse drug reaction. The results identify TLR4 as a potential therapeutic target for preventing cisplatin-induced hearing loss.