Female‐Specific Risk of <i>TAS2R</i> Variants in Chronic Rhinosinusitis: A Hospital‐Based Cohort Study From the Taiwan Precision Medicine Initiative

BACKGROUND: Bitter taste receptors (T2Rs) function in the innate immune defense of the sinonasal mucosa; however, the genetic association between the TAS2R gene family and chronic rhinosinusitis (CRS) remains understudied in Asian populations. This study aimed to investigate the impact of these genetic variants on CRS susceptibility using a large East Asian Han Chinese genomic database. METHODS: This retrospective case‒control study analyzed the Taiwan Precision Medicine Initiative dataset. We included 826 patients with CRS and 8260 control subjects. Controls were screened using ICD codes to exclude other upper airway disorders and were matched 1:10 to cases by age and sex. Univariable and multivariable logistic regression models, adjusted for relevant clinical covariates, were used to evaluate the independent effects of TAS2R genetic variants. We also conducted stratified analyses based on biological sex and clinical CRS phenotypes. RESULTS: Multivariable analysis identified TAS2R38 (rs77730028: adjusted odds ratio [aOR] = 1.363, p < 0.001) and TAS2R42 (rs1669424: aOR = 1.143, p = 0.039) as independent risk factors for CRS, whereas TAS2R1 (rs385: aOR = 0.912, p = 0.019) demonstrated a significant protective effect. Our study revealed a marked sexual dimorphism: these genetic associations were almost exclusively driven by the female cohort (in females, the risk effect of TAS2R38 reached an aOR of 1.709, p < 0.001, with no significant association observed in males). The risk effect of TAS2R38 remained consistent across both patients with CRS with nasal polyps and those without nasal polyps. CONCLUSION: Genetic variations within the TAS2R family significantly influence the risk of developing CRS in the Han Chinese population, demonstrating a specific female-driven effect. These findings help classify CRS endotypes and suggest that biological sex should be considered in future precision medicine and targeted therapeutic strategies.