Noise-induced Hearing Loss Susceptibility Research Articles

Interactions of genetic variations in FAS, GJB2 and PTPRN2 are associated with noise-induced hearing loss: a case-control study in China

BackgroundThis study aimed to screen and validate noise-induced hearing loss (NIHL) associated single nucleotide polymorphisms (SNPs), construct genetic risk prediction models, and evaluate higher-order gene-gene, gene-environment interactions for NIHL in Chinese population.MethodsFirst, 83 cases and 83 controls were recruited and 60 candidate SNPs were genotyped. Then SNPs with promising results were validated in another case-control study (153 cases and 252 controls). NIHL-associated SNPs were identified by logistic regression analysis, and a genetic risk model was constructed based on the genetic risk score (GRS), and classification and regression tree (CART) analysis was used to evaluate interactions among gene-gene and gene-environment.ResultsSix SNPs in five genes were significantly associated with NIHL risk (p < 0.05). A positive dose-response relationship was found between GRS values and NIHL risk. CART analysis indicated that strongest interaction was among subjects with age ≥ 45 years and cumulative noise exposure ≥ 95 [dB(A)·years], without personal protective equipment, and carried GJB2 rs3751385 (AA/AB) and FAS rs1468063 (AA/AB) (OR = 10.038, 95% CI = 2.770, 47.792), compared with the referent group. CDH23, FAS, GJB2, PTPRN2 and SIK3 may be NIHL susceptibility genes.ConclusionGRS values may be utilized in the evaluation of the cumulative effect of genetic risk for NIHL based on NIHL-associated SNPs. Gene-gene, gene-environment interaction patterns play an important role in the incidence of NIHL.

Noise-Induced Hearing Threshold Shift Correlated with Body Weight and External-Ear Amplification in Chinchilla: a Preliminary Analysis

BackgroundExternal-ear amplification (EEA) has been shown to vary from 5–19 dB-A in large datasets of pediatric, adolescent, and adult human participants. However, variable EEA is an overlooked characteristic that likely plays a role in individual noise-induced hearing loss (NIHL) susceptibility. A noise exposure varying 5–19 dB-A translates to high-EEA individuals theoretically experiencing 3–4 times greater NIHL risk than low-EEA individuals.ObjectiveThe purpose of this preliminary analysis was to test the hypothesis that higher EEA is correlated with increased noise-induced threshold shift susceptibility.DesignNine chinchillas were exposed to 4-kHz octave-band noise at 89 dB-SPL for 24 h. Auditory brainstem response thresholds were obtained pre-exposure, 24-h post-exposure, and 4-week post-exposure. Relationships between EEA and threshold shift were analyzed.ResultsOpen-ear EEA ranged 11–19 dB-SPL, and occluded-ear EEA ranged 10–21 dB-SPL. Higher occluded-ear EEA was correlated with increased NIHL susceptibility (p = 0.04), as was lower body weight (p = 0.01). Male animals exhibited more threshold shift than female animals (p = 0.02), lower body weight than female animals (p = 0.02), and higher occluded-ear EEA (male mean = 18 dB; female mean = 15 dB).ConclusionsTaken together, increased threshold shift susceptibility was observed in the smallest animals, animals with the highest occluded-ear EEA, and in male animals (which tended to have higher occluded-ear EEA). Given the established relationship between smaller body size and higher occluded-ear EEA, these preliminary results suggest that body size (and occluded-ear EEA; a function of body size) could be a potential, underlying driver of NIHL susceptibility differences, rather than true sex differences.

Whole-exome sequencing for screening noise-induced hearing loss susceptibility genes

Background High-throughput sequencing of genes indicating susceptibility to noise-induced hearing loss has not previously been reported. Aims/Objectives To identify and analyze genes associated with susceptibility to noise-induced hearing loss (NIHL) and characterize differences in susceptibility to hearing loss by genotype. Material and methods Pure tone audiometry tests were performed on 113 workers exposed to high-intensity noise. Whole-exome sequencing (WES) was conducted and NIHL susceptibility genes screened for training unsupervised and supervised machine learning models. Immunofluorescence staining of mouse cochlea was used to observe patterns of NIHL susceptibility gene expression. Results Participants were divided into a NIHL and a control group, according to the results of audiometry tests. Seventy-three possible NIHL susceptibility genes were input into the machine learning model. Two subgroups of NIHL could be distinguished by unsupervised machine learning and the classification was evaluated by the supervised machine learning algorithm. The VWF gene had the highest mutation frequency in the NIHL group and was expressed mainly in the spiral ligament. Conclusions and significance NIHL susceptibility genes were screened and NIHL subgroups could be distinguished. VWF may be a novel NIHL susceptibility gene.

Association of polymorphisms in the catalase gene with the susceptibility to noise-induced hearing loss: A meta-analysis

ObjectivesThe association between single nucleotide polymorphisms (SNPs) of the Catalase (CAT) gene and noise-induced hearing loss (NIHL) has been reported in several case-control studies. However, their conclusions are conflicting. This study aimed to determine the association between CAT genetic variants and NIHL susceptibility. MethodsWe searched PubMed, Embase, CNKI, Wanfang, and Web of Science for eligible English and Chinese studies published up to September 26, 2021. Studies reporting primary data that assessed the association between CAT SNPs and NIHL susceptibility were included. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). The odds ratio (OR), 95 % confidence interval (CI), and P value were calculated to assess the strength of the association. Publication bias was explored using funnel plots and Egger's test. ResultsOur meta-analysis included six articles involving 1428 patients and 2162 healthy controls. For rs208679, a significant association was detected in the allele model (A vs. G: OR = 0.81 [95 % CI, 0.67–0.97], P = 0.02) and the dominant model (AA vs. GG + AG: OR = 0.78 [95 % CI, 0.62–0.98], P = 0.03), but not in the heterozygote model, homozygote model, or the recessive model. For rs769217, rs7943316, and rs769214, no significant association was found in any genetic model. No significant publication bias was observed. ConclusionsThe rs208679 may be used in the Chinese population as a risk predictor for NIHL. While the rs769217, rs7943316, and rs769214 polymorphisms were not found to be associated with susceptibility to NIHL. Further studies with a larger population and higher quality are required to update the results.

Association between UBAC2 gene polymorphism and the risk of noise-induced hearing loss: a cross-sectional study.

The purpose of this article was to investigate the association between the ubiquitin-associated domain-containing protein 2 (UBAC2) gene polymorphism and noise-induced hearing loss (NIHL) and to further explore the role of single-nucleotide polymorphism (SNP) in UBAC2 in NIHL. A case control study involving 660 NIHL cases and 581 controls was conducted in this research. After genotyping by multiplex polymerase chain reaction (PCR) with next-generation sequencing, the correlation between SNPs and NIHL was analyzed using logistic regression analysis. Haplotype analysis was performed by Haploview 4.1 software. Then luciferase reporter assays and siRNA were used to explore the mechanism of SNPs in UBAC2 affecting NIHL susceptibility. The correlation analysis showed that rs3825427 AA genotype, rs9517701 GG genotype, rs7999348 GG genotype, and rs2296860 AA genotype were all associated with increased risk of NIHL (P < 0.05). The haplotype AGGA (rs3825427-rs9517701-rs7999348-rs2296860) also had a higher risk of NIHL (OR = 1.314; 95% CI, 1.098-1.572; P = 0.003). The results of the luciferase reporter assays showed that the fluorescence intensity of CTCF-OE + UBAC2 WT + TK was significantly higher than that of CTCF-NC + UBAC2 WT + TK and CTCF-OE + UBAC2 MT + TK (all P < 0.01). In CTCF knockdown cells, the expression of UBAC2 was also significantly downregulated (P = 0.0038), indicating that the transcription factor CTCF positively regulated the expression of UBAC2 and the rs3825427 C allele acted as an enhancer, which can promote CTCF to bind to the promoter of UBAC2, thereby promoting transcription. UBAC2 gene polymorphism is related to NIHL susceptibility. The UBAC2 rs3825427 regulates the expression level of UBAC2 by affecting the combination of CTCF and DNA, thus affecting the susceptibility of NIHL.

Noise-Induced Hearing Loss and Associated Genes

Noise-induced hearing loss (NIHL) is the most common occupational disease in the world and is the second most important cause of sensorineural hearing loss. Genetic and environmental factors are effective in the emergence of the disease. The World Health Organization (WHO) and the National Institute for Occupational Safety and Health (NIOSH) have classified NIHL as a research priority group. In this review, it is aimed to reveal the role of genetic variations and gene expression changes associated with susceptibility to noise-induced hearing loss in susceptibility to noise exposure. It can be said that genetic variations in heat shock protein 70 (Hsp70), 8-oxoG DNA glycosylase 1 (OGG1), Glutathione S-transferase M1 (GSTM1), catalase (CAT), Cadherin-23 (CDH23), Potassium Voltage Gated Channel Subfamily E Regulatory Subunit 1 (KCNE1) genes are associated with the risk of NIHL. Oxidative stress genes, inner ear potassium recycle pathway genes and monogenic hearing loss genes are accepted as candidate genes as genetic factors in NIHL. Individuals exposed to noise and at higher risk of developing NIHL are exposed to other environmental factors that interact with possible NIHL genes. More frequent use of high-throughput genotyping methods will allow the detection of multiple SNPs in a single sequence, making it possible to identify new NIHL susceptibility genes. This includes identifying individuals at high risk of developing NIHL and providing better hearing protection for susceptible individuals for noise-induced hearing loss. Thus, it could allow the development of genetic tests to help personalize treatment. Keywords: GBİK, occupational disease, genetic variations Special Issue of Health Sciences DOI: 10.7176/JSTR/7-08-07

Noise Exposure and Distortion Product Otoacoustic Emission Suprathreshold Amplitudes: A Genome-Wide Association Study

Background: Although several candidate-gene association studies have been conducted to investigate noise-induced hearing loss (NIHL) in humans, most are underpowered, unreplicated, and account for only a fraction of the genetic risk. Mouse genome-wide association studies (GWASs) have revolutionized the field of genetics and have led to the discovery of hundreds of genes involved in complex traits. The hybrid mouse diversity panel (HMDP) is a collection of classic inbred and recombinant inbred strains whose genomes have been either genotyped at high resolution or sequenced. To further investigate the genetics of NIHL, we report the first GWAS based on distortion product otoacoustic emission (DPOAE) measurements and the HMDP. Methods: A total of 102 strains (n = 635) from the HMDP were evaluated based on DPOAE suprathreshold amplitudes before and after noise exposure. DPOAE amplitude variation was set at 60 and 70 dB SPL of the primary tones for each frequency separately (8, 11.3, 16, 22.6, and 32 kHz). These values provided an indirect assessment of outer hair cell integrity. Six-week-old mice were exposed for 2 h to 10 kHz octave-band noise at 108 dB SPL. To perform local expression quantitative trait locus (eQTL) analysis, gene expression microarray profiles were generated using cochlear RNA from 64 hybrid mouse strains (n = 3 arrays per strain). Results: Several new loci were identified and positional candidate-genes associated with NIHL were prioritized, especially after noise exposure (1 locus at baseline and 5 loci after exposure). A total of 35 candidate genes in these 6 loci were identified with at least 1 probe whose expression was regulated by a significant cis-eQTL in the cochlea. After careful analysis of the candidate genes based on cochlear gene expression, 2 candidate genes were prioritized: Eya1 (baseline) and Efr3a (post-exposure). Discussion and Conclusion: For the first time, an association analysis with correction for population structure was used to map several loci for hearing traits in inbred strains of mice based on DPOAE suprathreshold amplitudes before and after noise exposure. Our results identified a number of novel loci and candidate genes for susceptibility to NIHL, especially the Eya1 and Efr3a genes. Our findings validate the power of the HMDP for detecting NIHL susceptibility genes.

Identifying genetic risk variants associated with noise-induced hearing loss based on a novel strategy for evaluating individual susceptibility

BackgroundThe overall genetic profile for noise-induced hearing loss (NIHL) remains elusive. Herein we proposed a novel machine learning (ML) based strategy to evaluate individual susceptibility to NIHL and identify the underlying genetic risk variants based on a subsample of participants with extreme phenotypes. MethodsFive features (age, sex, cumulative noise exposure [CNE], smoking, and alcohol drinking status) of 5,539 shipbuilding workers from large cross-sectional surveys were included in four ML classification models to predict their hearing levels. The area under the curve (AUC) and prediction accuracy were exploited to evaluate the performance of the models. Based on the prediction error of the ML models, the NIHL-susceptible group (n=150) and NIHL-resistant group (n=150) with a paradoxical relationship between hearing levels and features were separately screened, to identify the underlying variants associated with NIHL risk using whole-exome sequencing (WES). Subsequently, candidate risk variants were validated in an additional replication cohort (n=2108), followed by a meta-analysis. ResultsWith 10-fold cross-validation, the performances of the four ML models were robust and similar, with average AUCs and accuracies ranging from 0.783 to 0.798 and 73.7% to 73.8%, respectively. The phenotypes of the NIHL-susceptible and NIHL-resistant groups were significantly different (all p<0.001). After WES analysis and filtering, 12 risk variants contributing to NIHL susceptibility were identified and replicated. The meta-analyses showed that the A allele of CDH23 rs41281334 (odds ratio [OR]=1.506, 95% confidence interval [CI]=1.106-2.051) and the C allele of WHRN rs12339210 (OR=3.06, 95% CI=1.398-6.700) were significantly associated with increased risk of NIHL after adjustment for confounding factors. ConclusionsThis study revealed two genetic variants in CDH23 rs41281334 and WHRN rs12339210 that associated with NIHL risk, based on a promising approach for evaluating individual susceptibility using ML models.

Modeling individual noise-induced hearing loss risk with proxy measurements of external-ear amplification.

Significant variability in noise-induced hearing loss (NIHL) susceptibility suggests there are factors beyond sound level and duration of exposure that contribute to individual susceptibility. External-ear amplification (EEA) from external-ear structures varies significantly due to ear size and shape, potentially influencing NIHL susceptibility. This study tested the hypothesis that EEA can be predicted using non-technical proxy measurements including pinna height (cm), body height (m), and earcanal volume (cm3). 158 participants (4-78 years) completed otoscopy, tympanometry, pinna measurements, body height measurements, and two EEA measurements: (1) total real-ear unaided gain (REUG) of the open ear and (2) real-ear to coupler difference (RECD), representing unaided gain from the earcanal. Participants' individual noise doses were compared in hypothetical exposures. REUG ranged from 5 to 19 dBA and was correlated with pinna height. High-REUG participants were estimated to accrue noise doses at least 5 times higher than low-REUG participants. RECD ranged from 7 to 24 dBA and was correlated with earcanal volume and body height. The results support the hypothesis that EEA measurement could significantly improve estimation of an individual's position along the NIHL risk spectrum. Non-technical proxy measurements of EEA (pinna height, body height, earcanal volume) were statistically significant but yielded high variability in individual EEA prediction.

A functional SNP in miR-625-5p binding site of AKT2 3'UTR is associated with noise-induced hearing loss susceptibility in the Chinese population.

The purposes of the current study were to investigate the association of a few of single nucleotide polymorphisms (SNPs) within the AKT2 gene and noise-induced hearing loss (NIHL) susceptibility and explore the potential mechanism underlying NIHL. Three SNPs (rs2304186, rs41275750, and rs76524493) were genotyped in a Chinese population which consists of 690 NIHL patients and 650 normal hearing controls. Bioinformatic analysis was conducted to predict the potential miRNA-binding site of SNPs. Plasmid construction, cell transfection, and dual-luciferase reporter assay were performed to investigate the potential molecular mechanism of SNPs involving in NIHL. The results revealed that rs2304186 GT genotype (OR = 1.41; 95% CI = 1.09-1.83) and TT genotype (OR = 1.51; 95% CI = 1.08-2.10) imparted increased risk of NIHL, and the increased risk could also be found in a dominant model (OR = 1.44; 95% CI = 1.12-1.84). The stratification analysis showed that rs2304186 GT/TT conferred a higher risk for NIHL, especially in subgroups of male, age (35-45 and > 45 years), noise exposure time (> 16 years), and noise exposure level (≤ 85 and ≥ 92 dB), when GG genotype as a reference. Furthermore, the haplotype TCCTACT (rs2304186-rs41275750-rs76524493) was found to be significantly associated with a high risk of NIHL (OR = 1.19; 95% CI = 1.02-1.40). Functional experiments showed that rs2304186 G allele combined with hsa-miR-625-5p mimics could significantly decrease the luciferase activity compared with T allele, indicating that rs2304186 altered the binding affinity of hsa-miR-625-5p to SNP rs2304186 mutation region, thus directly targeting AKT2 gene. In conclusion, our study provides evidence for the first time that SNP rs2304186 of AKT2 3'UTR might affect NIHL susceptibility by altering the binding affinity of has-miR-625-5p to mutation region in an allele-specific manner and it may act as a potential biomarker of NIHL susceptibility.

CARD8 polymorphism rs2043211 protects against noise-induced hearing loss by causing the dysfunction of CARD8 protein.

Inflammation is a complicated process and is considered to be responsible for the development of noise-induced hearing loss (NIHL). CARD8 is an important component of inflammasome that has been implicated in inflammation. To decide the relationship between the polymorphisms of CARD8 gene and NIHL risk and deduce the potential mechanism, three SNPs (rs2043211, rs1062808, and rs12459322) were genotyped in a Chinese population consisting of 610 NIHL cases and 612 normal hearing controls. The possible impacts of SNPs on CARD8 structure and function were assessed using a variety of bioinformatics tools. Plasmids expressing wild-type and/or mutated CARD8 were transfected into HEK293 cells to verify the effect of SNPs on CARD8 protein expression level by western blot. The results revealed that rs2043211 AA genotype and A allele were associated with decreased risk of NIHL. Stratified analysis found that the male, drinking and exposed to noise ≥ 92dB, subjects harboring rs2043211 A allele had a low risk of NIHL. The haplotype AGG (rs2043211-rs1062808-rs12459322) was significantly associated with a decreased risk of NIHL. SNP rs2043211 was predicted to be deleterious and affects CARD8 protein structure and stability. Furthermore, the functional experiment showed the mutant CARD8 could significantly decrease the CARD8 protein expression level. This study confirms that rs2043211 A allele may reduce NIHL risk by causing the loss of PPI combined with the decreased CARD8 expression level leading to CARD8 functional changes, and it may be one valuable genetic biomarker of NIHL susceptibility for Chinese noise-exposed workers.

Association between single nucleotides polymorphism of catalase gene and susceptibility to noise-induced hearing loss in occupational population

To investigate the relationship between single nucleotides polymorphism of catalase(CAT) gene and susceptibility to noise-induced hearing loss(NIHL) in occupational noise exposed population. A case-control study of 1∶1 was conducted to select 286 workers with binaural high frequency average hearing threshold ≥40 dB(HL), from 2006 to 2015 in a cohort study of occupational noise exposure workers in Henan Province. According to the type of work, the age difference was not more than 5 years and the length of exposure to noise was not more than 2 years. The polymorphism of 8 single nucleotides in CAT gene was detected by medium SNPscanTM, and the relationship between 8 single nucleotides polymorphism of CAT gene and NIHL susceptibility was analyzed by multivariate conditional logistic regression. Under the dominant model of rs208679 locus of CAT gene [(GA GG)/AA], the risk of NIHL in individuals carrying GA or GG genotype was 1. 431 times higher than that in individuals carrying AA genotype(95%CI 1. 020-2. 009), and P=0. 038. G, a mutant at rs208679 site of CAT gene, may be one of the risk factors for NIHL susceptibility.

Salt-Inducible Kinase 3 Haplotypes Associated with Noise-Induced Hearing Loss in Chinese Workers

Introduction: Noise-induced hearing loss (NIHL) is a common occupational disease that represents an irreversible hearing damage to the auditory system. It has been identified as a complicated disease involving both environmental and genetic factors. More efforts need to be made to explore the genes associated with susceptibility to NIHL. The main aim of this research is to detect the associations between SIK3 polymorphisms and NIHL susceptibility in Han people in China. Methods: A case-control study was performed in 586 cases and 639 controls in a textile factory matched for sex, age, smoking, drinking, work time with noise, and intensity of noise exposure. Three single nucleotide polymorphisms (SNPs) (rs493134, rs6589574, and rs7121898) of SIK3 were genotyped in the participants. Then, the main influences of the SNPs on and their interactions with NIHL were assessed. Results: Under the allelic model, distributions of rs493134 T, rs6589574 G, and rs7121898 A in the NIHL group are statistically different from those of the normal group (p = 0.001, p < 0.001, and p = 0.019, respectively). The following haplotype analysis shows that TAA (rs493134-rs6589574-rs7121898) may have a protective effect, while TGA (rs493134-rs6589574-rs7121898) (OR = 1.49, 95% CI = 1.25–1.79) may be a risk factor for NIHL. Multifactor dimensionality reduction analysis shows that the interaction of the 3 selected SNPs is associated with NIHL susceptibility (OR = 1.88, 95% CI = 1.50–2.36). Conclusion: The results suggest that 3 SNPs (rs493134, rs6589574, and rs7121898) of SIK3 may be an important part of NIHL susceptibility and can be applied in the prevention, early diagnosis, and treatment of NIHL in noise-exposed Chinese workers.

Single-Nucleotide Polymorphisms in XPO5 are Associated with Noise-Induced Hearing Loss in a Chinese Population.

ObjectivesThe purpose of this study was to investigate the correlation between single-nucleotide polymorphism (SNP) in 3′UTR of XPO5 gene and the occurrence of noise-induced hearing loss (NIHL), and to further explore the regulatory mechanism of miRNAs in NIHL on XPO5 gene and the occurrence of noise-induced hearing loss (NIHL), and to further explore the regulatory mechanism of miRNAs in NIHL on MethodsWe conducted a case-control study involving 1040 cases and 1060 controls. The effects of SNPs on XPO5 gene and the occurrence of noise-induced hearing loss (NIHL), and to further explore the regulatory mechanism of miRNAs in NIHL on ResultsWe genotyped four SNPs (rs2257082, rs11077, rs7755135, and rs1106841) in the XPO5 gene and the occurrence of noise-induced hearing loss (NIHL), and to further explore the regulatory mechanism of miRNAs in NIHL on XPO5 gene and the occurrence of noise-induced hearing loss (NIHL), and to further explore the regulatory mechanism of miRNAs in NIHL on XPO5 gene and the occurrence of noise-induced hearing loss (NIHL), and to further explore the regulatory mechanism of miRNAs in NIHL on XPO5. Conclusion. The genetic polymorphism, rs11077, within XPO5 is associated with the risk of noise-induced hearing loss in a Chinese population.XPO5 gene and the occurrence of noise-induced hearing loss (NIHL), and to further explore the regulatory mechanism of miRNAs in NIHL on

Research and Discussion on the Relationships between Noise-Induced Hearing Loss and ATP2B2 Gene Polymorphism

Long-term and continuous noise exposure can result in noise-induced hearing loss (NIHL), which is a worldwide problem resulting from the interaction of environmental and genetic factors. The ATP2B2 gene polymorphism can destroy cochlear hair cells and increase the risk of NIHL. A case-control study of 760 Chinese textile workers was conducted to investigate the relationship between ATP2B2 polymorphisms and NIHL susceptibility. Venous blood was collected and questionnaires were conducted by professional physicians. A case group and a control group which were typed by individuals' pure-tone audiometry test results were set. Three polymorphism sites of ATP2B2 were genotyped by using the PCR technique. Analysis results revealed that the C allele of rs3209637 (95%CI = 1.08–2.58, odds ratio (OR) = 1.67, P = 0.027) was a dangerous factor and could add to risks of NIHL in the Chinese employees. The data of stratified analysis revealed that individuals who are exposed to noise > 95 dB with the rs3209637 C genotype have a higher susceptibility to NIHL (OR = 1.34, 95%CI = 1.07–1.68). Multifactor dimensionality reduction analysis revealed that the interaction between rs14154 and rs3209637 is linked to increased NIHL risk, and for the interaction among rs14154, smoking and drinking had the same function (OR = 1.54 and 1.77, 95%CI = 1.15–2.07, 1.33–2.37, and P = 0.0037 and P < 0.0001, respectively). Our results suggest that genetic polymorphism rs3209637 C within ATP2B2 is a risk factor for NIHL among Chinese employees and rs3209637 C could be a potential biomarker for NIHL patients.

Screening of noise-induced hearing loss (NIHL)-associated SNPs and the assessment of its genetic susceptibility

BackgroundThe aim of this study was to screen for noise-induced hearing loss (NIHL)-associated single nucleotide polymorphisms (SNPs) and to construct genetic risk prediction models for NIHL in a Chinese population.MethodsFour hundred seventy-six subjects with NIHL and 476 matched controls were recruited from a cross-sectional survey on NIHL in China. A total of 83 candidate SNPs were genotyped using nanofluidic dynamic arrays on a Fluidigm platform. NIHL-associated SNPs were screened with a multiple logistic model, and a genetic risk model was constructed based on the genetic risk score (GRS). The results were validated using a prospective cohort population.ResultsSeven SNPs in the CDH23, PCDH15, EYA4, MYO1A, KCNMA1, and OTOG genes were significantly (P < 0.05) associated with the risk of NIHL, whereas seven other SNPs were marginally (P > 0.05 and P < 0.1) associated with the risk of NIHL. A positive correlation was observed between GRS values and odds ratio (OR) for NIHL. Two SNPs, namely, rs212769 and rs7910544, were validated in the cohort study. Subjects with higher GRS (≧9) showed a higher risk of NIHL incidence with an OR of 2.00 (95% CI = 1.04, 3.86).ConclusionsGenetic susceptibility plays an important role in the incidence of NIHL. GRS values, which are based on NIHL-associated SNPs. GRS may be utilized in the evaluation of genetic risk for NIHL and in the determination of NIHL susceptibility.

Association of polymorphisms in heat shock protein 70 genes with the susceptibility to noise-induced hearing loss: A meta-analysis.

BackgroundSeveral case-control studies reported the relationship between single nucleotide polymorphisms (SNPs) in HSP70 genes and noise-induced hearing loss (NIHL). However, their conclusions are conflicting. This meta-analysis aims to identify the association of HSP70 variants and NIHL susceptibility.MethodA systematical literature search was performed in PubMed, Web of Science, EMBASE, and Wanfang Chinese database. The pooled odds radio (OR), 95% confidence interval (CI) and p value were calculated in fixed- or random-effects model according to the I2 value in the heterogeneity test.ResultsFour articles containing five studies, including 633 cases and 926 controls, were included. Under the allele, homozygote and dominant model, the pooled ORs (95%CI, p-value) of rs1061581 were 1.32 (1.06–1.67, p = 0.019), 1.93 (1.10–3.36, p = 0.021) and 1.455 (1.408–2.019, p = 0.025), respectively. In addition, a significant association was found between rs2227956 in Caucasians and the NIHL susceptibility under all five genetic models. We did not discover evidence sufficient to prove the associations between the other three SNPs (rs1043618, rs2763979 and rs2075800) and the NIHL susceptibility.ConclusionThis meta-analysis indicated that the two HSP70 variants, rs1061581 and rs2227956, may serve as genetic susceptibility factors for NIHL. Larger scale studies are required to further update the results.

The Genetic Architecture of Noise-Induced Hearing Loss: Evidence for a Gene-by-Environment Interaction.

The discovery of environmentally specific genetic effects is crucial to the understanding of complex traits, such as susceptibility to noise-induced hearing loss (NIHL). We describe the first genome-wide association study (GWAS) for NIHL in a large and well-characterized population of inbred mouse strains, known as the Hybrid Mouse Diversity Panel (HMDP). We recorded auditory brainstem response (ABR) thresholds both pre and post 2-hr exposure to 10-kHz octave band noise at 108 dB sound pressure level in 5–6-wk-old female mice from the HMDP (4–5 mice/strain). From the observation that NIHL susceptibility varied among the strains, we performed a GWAS with correction for population structure and mapped a locus on chromosome 6 that was statistically significantly associated with two adjacent frequencies. We then used a “genetical genomics” approach that included the analysis of cochlear eQTLs to identify candidate genes within the GWAS QTL. In order to validate the gene-by-environment interaction, we compared the effects of the postnoise exposure locus with that from the same unexposed strains. The most significant SNP at chromosome 6 (rs37517079) was associated with noise susceptibility, but was not significant at the same frequencies in our unexposed study. These findings demonstrate that the genetic architecture of NIHL is distinct from that of unexposed hearing levels and provide strong evidence for gene-by-environment interactions in NIHL.

Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene.

PDZD7 was identified in 2009 in a family with apparent nonsyndromic sensorineural hearing loss. However, subsequent clinical reports have associated PDZD7 with digenic Usher syndrome, the most common cause of deaf-blindness, or as a modifier of retinal disease. No further reports have validated this gene for nonsyndromic hearing loss, intuitively calling correct genotype-phenotype association into question. This report describes a validating second case for biallelic mutations in PDZD7 causing nonsyndromic mild to severe sensorineural hearing loss. It also provides detailed audiometric and ophthalmologic data excluding Usher syndrome in both the present proband (proband 1) and the first proband described in 2009 (proband 2). Proband 1 was sequenced using a custom-designed next generation sequencing panel consisting of 151 deafness genes. Bioinformatics analysis and filtering disclosed two PDZD7 sequence variants (c.1648C>T, p.Q550* and c.2107del, p.S703Vfs*20). Segregation testing followed in the family. For both probands, audiograms were collected and analyzed for progressive hearing loss and detailed ophthalmic evaluations were performed including electroretinography. Proband 1 demonstrated a prelingual, nonsyndromic, sensorineural hearing loss that progressed in the higher frequencies between 4 and 9 years old. PDZD7 segregation analysis confirmed biallelic inheritance (compound heterozygosity). Mutation analysis determined the c.1648C>T mutation as novel and reported the c.2107del deletion as rs397516633 with a calculated minor allele frequency of 0.000018. Clinical evaluation spanning well over a decade in proband 2 disclosed bilateral, nonprogressive hearing loss. Both probands showed healthy retinas, excluding Usher syndrome-like changes in the eye. PDZD7 is confirmed as a bona fide autosomal recessive nonsyndromic hearing loss gene. In both probands, there was no evidence of impaired vision or ophthalmic pathology. As the current understanding of PDZD7 mutations bridge Mendelian and complex phenotypes, the authors recommend careful variant interpretation, since PDZD7 is one of many genes associated with both Usher syndrome and autosomal recessive nonsyndromic hearing loss. Additional reports are required for understanding the complete phenotypic spectrum of this gene, including the possibility of high-frequency progression, as well as noise-induced hearing loss susceptibility in adult carriers. This report rules out all forms of Usher syndrome with an onset before 12 and 15 years old in probands 1 and 2, respectively. However, due to the young ages of the probands, this report is uninformative regarding older patients.

Association between GPX-1 single nucleotide polymorphisms and susceptibility to noise-induced hearing loss among Chinese Han population

To investigate the association between single nucleotide polymorphisms (SNPs) in glutathione peroxidase 1 (GPX-1) gene, rs3448, rs1050450, rs1800668, and rs1987628, and the susceptibility to noise-induced hearing loss (NIHL) among Chinese Han population. A case-control study was conducted to investigate the threshold shift of the left ear at 3000 Hz among the workers of Chinese Han population who were exposed to the same level of sound pressure. Two hundred and one (10%) of the subjects with the highest level of threshold shift were recruited in susceptible group, while 202 of (10%) of the subjects with the lowest level of threshold shift were recruited in tolerant group. Targeted occupational health survey and questionnaire survey were performed among these people. For each individual, genome DNA was extracted from 5 ml of fasting peripheral venous blood. Four SNPs (GPX-1 rs3448, rs1050450, rs1800668, and rs1987628) were genotyped by the TaqMan SNP genotyping kit. The main effects of SNPs and the association between NIHL susceptibility and SNPs were analyzed by logistic regression. The C allele of rs1987628 was a risk factor for NIHL, with an odds ratio (OR) of 2.531 (95%CI: 1.878-3.411) as compared with the T allele. The CC genotype of rs1987628 was more associated with NIHL than the TT genotype (OR = 3.500, 95% CI: 1.984-6.174; adjusted OR = 3.544, 95% CI: 1.974 ∼ 6.364). Among Chinese Han population, GPX-1 SNP rs1987628 may be associated with the susceptibility to NIHL.