Susceptibility genes for gentamicin-induced vestibular dysfunction

Background: Approximately 5% of patients administered gentamicin (GM), an aminoglycoside antibiotic, experience vestibular ototoxicity resulting in balance dysfunction. In the present study, we sought to identify susceptibility genes associated with GM-induced vestibular dysfunction using a case/control design. Methods: 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. Candidate genes were identified primarily for their roles in oxidative stress based on predicted mechanisms of gentamicin-induced ototoxicity. 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 the NOS3 (ENOS) p. Glu298Asp polymorphism as significantly associated with GM-induced vestibular dysfunction (both p <= 0.03). MDR analysis revealed a three-gene combination, consisting of NOS3 (p. Glu298Asp), GSTZ1 (p. Lys32Glu), and GSTP1 (p. Ile105Val), that provided the highest predictive model for GM-induced vestibular dysfunction (64% accuracy; p = 0.009). Conclusions: The results indicate that carriers of risk alleles at three oxidative stress-related genes have increased susceptibility to GM-induced vestibular dysfunction.