Dataset Information

Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

ABSTRACT: In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL) of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP) to a 10 kHz octave band noise at 108 dB for 2 hours and assessed the permanent threshold shift 2 weeks post exposure using frequency specific stimuli. These data were then used in a genome-wide association study (GWAS) using the Efficient Mixed Model Analysis (EMMA) to control for population structure. In this manuscript we describe our GWAS, with an emphasis on a significant peak for susceptibility to NIHL on chromosome 17 within a haplotype block containing NADPH oxidase-3 (Nox3). Our peak was detected after an 8 kHz tone burst stimulus. Nox3 mutants and heterozygotes were then tested to validate our GWAS. The mutants and heterozygotes demonstrated a greater susceptibility to NIHL specifically at 8 kHz both on measures of distortion product otoacoustic emissions (DPOAE) and on auditory brainstem response (ABR). We demonstrate that this sensitivity resides within the synaptic ribbons of the cochlea in the mutant animals specifically at 8 kHz. Our work is the first GWAS for NIHL in mice and elucidates the power of our approach to identify tonotopic genetic susceptibility to NIHL.

SUBMITTER: Lavinsky J

PROVIDER: S-EPMC4399881 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

Lavinsky Joel J Crow Amanda L AL Pan Calvin C Wang Juemei J Aaron Ksenia A KA Ho Maria K MK Li Qingzhong Q Salehide Pehzman P Myint Anthony A Monges-Hernadez Maya M Eskin Eleazar E Allayee Hooman H Lusis Aldons J AJ Friedman Rick A RA

PLoS genetics 20150416 4

In the United States, roughly 10% of the population is exposed daily to hazardous levels of noise in the workplace. Twin studies estimate heritability for noise-induced hearing loss (NIHL) of approximately 36%, and strain specific variation in sensitivity has been demonstrated in mice. Based upon the difficulties inherent to the study of NIHL in humans, we have turned to the study of this complex trait in mice. We exposed 5 week-old mice from the Hybrid Mouse Diversity Panel (HMDP) to a 10 kHz o ...[more]

PMID: 25880434

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Project description:BACKGROUND:Noise-induced hearing loss (NIHL) is a complex disease caused by environmental and genetic risk factors. This study was to explore the association of noise kurtosis, triphosphopyridine nucleotide oxidase 3 (NOX3) and lifestyles with NIHL. METHODS:This case-control study included 307 patients with NIHL and 307 matched control individuals from Zhejiang province of China. General characteristics, noise exposure data, the exfoliated cells of the oral mucosa, and lifestyle details of individuals were collected. The kompetitive allele specific polymerase chain reaction (KASP) method was used to analyze the genotypes of three single nucleotide polymorphisms (SNPs) of NOX3. RESULTS:People who exposed to complex noise had a higher risk of NIHL than those exposed to steady noise (adjusted: OR = 1.806, P = 0.002). The GT genotype of additive model and TT + GT genotype of dominant model in NOX3 rs12195525 decreased the risk of NIHL (adjusted: OR = 0.618, P = 0.043; OR = 0.622, P = 0.036). Smoking and exposure to high video volume increased the risk of NIHL (adjusted: OR = 1.486, P = 0.038; OR = 1.611, P = 0.014). Oppositely, regular physical exercise decreased the risk of NIHL (adjusted: OR = 0.598, P = 0.004). A positive interaction was found between complex noise and lifestyles including high video volume exposure and no physical exercise in the additive models (RERI = 1.088, P < 0.001; RERI = 1.054, P = 0.024). A positive interaction was also found between NOX3 rs12195525 GG genotype and lifestyles including smoking and high video volume exposure in the additive models (RERI = 1.042, P = 0.005; RERI = 0.774, P = 0.044). CONCLUSIONS:Noise temporal structure, NOX3 rs12195525 polymorphism, and the three lifestyles of smoking, video volume, and physical exercise were related to the NIHL. There were the interactions between noise temporal structure and the lifestyle of video volume or physical exercise, as well as between NOX3 and the lifestyle of smoking or video volume. These results provide a theoretical basis for the prevention and genetic testing of NIHL.

Dataset Information

Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

Publications

Genome-wide association study identifies nox3 as a critical gene for susceptibility to noise-induced hearing loss.

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