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PURPOSE: To identify susceptibility genes associated with gentamicin-(GM; an aminoglycoside antibiotic) induced vestibular dysfunction. METHODS: A case/control analysis was performed. White cases (n=137; 55 men, 82 women) were recruited based on physician-confirmed unilateral or bilateral vestibular dysfunction attributed to GM administration. Controls (n=126; 54 men, 72 women) were healthy, age-matched individuals without vestibular dysfunction or balance impairment. Buccal cell samples were obtained from all subjects and DNA was genotyped for 15 polymorphisms in 9 genes. Statistical analyses included the multi-dimensionality reduction (MDR) method for identifying gene x gene interactions across multiple candidate genes. RESULTS: Both single gene and MDR analyses revealed that the ENOS Glu298Asp polymorphism was significantly associated with GM-induced vestibular dysfunction (both P<0.05). MDR analysis revealed a three-gene combination, consisting of ENOS (Glu298Asp), GSTZ1 (Lys32Glu), and GSTP1 (Ile105Val), that provided the highest predictive model for GM-induced vestibular dysfunction (64% accuracy; p=0.001). CONCLUSION: The results indicate that carriers of risk alleles at three oxidative stress-related genes have increased susceptibility to GM-induced vestibular dysfunction. [ABSTRACT FROM AUTHOR]