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 <or= 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.
Roth
Stephen M
SM
Department of Kinesiology, School of Public Health, University of Maryland, College Park, MD 20742-2611, USA. sroth1@umd.edu
Williams
Scott M
SM
Jiang
Lan
L
Menon
Kalapurakkal S
KS
Jeka
John J
JJ
D000368:Aged; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005839:Gentamicins / Q000009:adverse effects; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic; D004856:Postural Balance / Q000187:drug effects; D012016:Reference Values; D012678:Sensation Disorders / Q000139:chemically induced / Q000235:genetics*; D015837:Vestibular Diseases / Q000139:chemically induced / Q000235:genetics*
D000900:Anti-Bacterial Agents; D005839:Gentamicins; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C407705:GSTZ1 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase
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