Affiliations: [a] Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742, USA | [b] Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD 20742, USA | [c] Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37240, USA
Correspondence:
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Corresponding author: Stephen M. Roth, Ph.D., 2134 SPH Building, Department of Kinesiology, University of Maryland, College Park, MD 20742-2611, USA. Tel.: +1 301 405 2504; Fax: +1 301 405 5578; E-mail: [email protected]
Abstract: 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.
