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Full-Text PDF: 965-968.pdf
Gene-Gene Interaction of GJB2, SOD2, and CAT on Occupational Noise-induced Hearing Loss in Chinese Han Population
 

Letter to the Editor

Gene-Gene Interaction of GJB2, SOD2, and CAT on Occupational Noise-induced Hearing Loss in Chinese Han Population

WANG Sheng Li1,2, YU Lu Gang2, LIU Ren Ping2, ZHU Wan Zhan2, GAO Wei Min2, XUE Li Ping2, JIANG Xu2, ZHANG Ya Han2, YI Ding2, CHEN Dong1,#, and ZHANG Yong Hong1,#

doi: 10.3967/bes2014.131

1. Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou 215123, Jiangsu, China; 2. Suzhou Industrial Park Centers for Disease Control and Prevention (Institute of Health Inspection and Supervision), Suzhou 215021, Jiangsu, China


The effects of genetic factors on the noise-induced hearing loss (NIHL) are still unclear. In the present study, eight single-nucleotide polymorphisms (SNPs) included rs1227049 and rs3802711 (CDH23), rs1695 (GSTP1), rs137852540 (GJB2), rs2289274 (PMCA2), rs4880 (SOD2), rs7943316, and rs769214 within CAT that might associated with NIHL were further validated in Chinese workers. The results showed that the carriers of the T allele (AT+TT) of rs7943316 and A allele (GA+AA) of rs769214, were significantly associated with an increased risk of NIHL compared to those with AA genotype (P<0.05) and GG genotype (P<0.05). Moreover, a significant three-locus model (P=0.0107) involving rs2016520, rs9794, and rs1805192 were observed that might associated with NIHL, with 53.95% of testing accuracy. Thus, our present study provided the evidence that GJB2, SOD2, and CAT genes might account for the NIHL development in independently and/or in an interactive manner.

Noise is the most important environmental factor and the most frequent occupational hazard. Long-term exposed to loud noise or excessively loud impulse noise might damage hair cells of Corti in the inner ear, and eventually cause noise-induced hearing loss (NIHL). It has been estimated that more than 600 million workers are exposed workplace noise worldwide, especially in countries with growing industrial activity. However, susceptibility to noise damages differs remarkably among individuals, indicating that NIHL is a complex disease and  induced by a combination of environmental and genetic factors[1]. The association studies on the NIHL patients indicated that oxidative stresses genes SOD2, CAT, GSTP1, and GSTT1 as putative NIHL susceptibility genes in Swedish and Chinese workers[2-3]. Additionally, genes encoding proteins involved in the potassium recycling pathway such as GJB2 and Cadherin23 (CDH23) gene, a component of inter-stereocilia links on cochlear hair cells, were significantly associated with NIHL in different studies[4-5].

Until now, the genetic factors involved in NIHL have still not been well defined and many results from the previous studies cannot be replicated[6]. In order to further validate the associations in previously identified SNPs of those candidate genes with NIHL, we analyzed the SNPs in CDH23, GSTP1, GJB2, PMCA2, SOD2, and CAT genes, and gene-gene interactions among of them that might account for NIHL development in a group of Chinese workers occupationally exposed to noise.

This study was approved by the Regional Bioethical Committee at the Soochow University. Totally, 611 Chinese male workers (466 normal hearing workers and 145 NIHL workers) were gathered from an electric power station and a glass bottle factory in Suzhou, China. All of the participants had been continuously employed in the pants for at least three years. At their workplace, they were exposed to continuous and steady-state noise at the mean equivalent level Leq=84.5±3.01 dBA. All participants underwent an audiometric examination. Individuals were excluded from the study if they had a history of head trauma, exposure to ototoxic drugs or substances, or diseases known to cause hearing impairment (such as hereditary deafness, middle ear inflammation, meningitis, mumps, other viral infections).

Eight single-nucleotide polymorphisms (SNPs) included rs1227049 and rs3802711 (CDH23), rs1695 (GSTP1), rs137852540 (GJB2), rs2289274 (PMCA2), rs4880 (SOD2), rs7943316, and rs769214 within CAT were selected presently based on known heterozygosity and a minor allele frequency (MAF)  >0.05. SNPs genotyping was determined by using the SEQUENOM Mass ARRAY matrix-assisted laser desorption ionization-time of flight mass spectrometry platform (Sequenom, San Diego, CA).

Hardy-Weinberg equilibrium was assessed within controls using the goodness-of-fit χ2 test. The distribution of the general characteristics between NIHL subjects and non-NIHL controls was compared by using two-sided Chi-square test. The significance level was set at P<0.05. A linear regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between genotypes and NIHL. For quality control purpose, Hardy-Weinberg equilibrium (HWE) test was used to detect genotype typing errors by Fisher’s exact test. Linkage disequilibrium (LD) between polymorphisms was estimated by using SHEsis (available online at http://analysis.bio-x.cn). Furthermore, GMDR software (version 1.0.1) was applied for further detecting gene-gene interactions associated with NIHL. The testing balanced accuracy is the measure of the degree to which the interaction accurately predicts NIHL value with scores between 0.50 (indicating that the model predicts no better than chance) and 1.00 (indicating perfect prediction). Finally, a sign test or a permutation test (providing empirical P values) for prediction accuracy can be used to measure the significance of an identified model.

Of 611 male workers recruited in the present study, 350 subjects were selected from an electric power station and 82 persons were diagnosed as NIHL, 261 participants came from a glass bottle factory, and 63 of them were diagnosed as NIHL. No significant difference was observed between the persons from electric power station and glass bottle factory. Moreover, no significant differences of age (27.60±5.67 vs. 27.23±5.49 yrs), exposure time to noise (4.59±3.66 vs. 4.54±4.11 yrs) and exposure levels of noise (83.7±4.01 vs. 84.8±3.27 dBA) were observed between the subjects with or without NIHL.

As shown in Table 1, there was no significant difference of the SNPs distributions between NIHL persons and normal control. After adjustment for age, exposure noise level and exposure time to noise,


Table 1. Distributions of the eight SNPs genotypes in NIHL persons and normal control

Variabilities

Individuals with Normal Hearing (n=456)

Individuals with NIHL (n=145)

P Value

CDH23

rs1227049

 

 

0.51

GG/GC/CC

220/200/36

62/71/12

 

C (%)

7.9

8.3

 

CDH23

rs3802711

 

 

0.81

CC/CT/TT

276/158/22

92/47/6

 

T (%)

4.8

4.1

 

GSTP1

rs1695

 

 

0.15

AA/AG/GG

293/153/10

92/45/8

 

G (%)

2.2

5.5

 

GJB2

rs137852540

 

 

 

AA/AG/GG

256/166/34

84/54/7

0.55

G (%)

7.5

4.8

 

PMCA2

rs2289274

 

 

0.97

GG/GA/AA

234/181/41

74/57/14

 

A (%)

9

9.7

 

SOD2

rs4880

 

 

0.78

TT/TC/CC

330/120/6

106/36/3

 

C (%)

1.3

2.1

 

CAT

rs7943316

 

 

0.05

AA/AT/TT

223/197/36

57/69/19

 

T (%)

7.9

13.1

 

 

rs769214

 

 

0.06

CAT

GG/GA/AA

223/196/37

57/69/19

 

 

A (%)

8.1

13.1

 


the linear regression analysis results showed that the carriers of the T allele (AT+TT, dominant model) of rs7943316 and A allele (GA+AA) of rs769214, were significantly associated with an increased risk of NIHL compared to the carriers of the AA genotype (mean difference=1.48, 95% CI=1.01-2.16, P=0.04) and the carriers of the GG genotype (mean difference=1.48, 95% CI=1.01-2.16, P=0.04), respectively (Table 2). These results were similar to the previous studies. The findings from two large independent populations from Sweden and Poland reported that the polymorphisms of CAT gene are NIHL susceptibility genes and their effects can be detected if noise exposure levels are taken into account[7]. However, we were not able to validate the relationships between the risks of NIHL and the other six SNPs that previously published. Therefore, investigate replication is still needed to investigated the genetic associations with NIHL and extend them to different population.

NIHL is well known as a multi-factorial disease thus probably involving multiple SNPs in a variety of genes. The investigation of gene-gene interaction surely will expand our current understanding of gene-

tics effects on NIHL. Therefore, we employed the GMDR analysis in the present study to assess the impact of the interaction among the eight SNPs, after adjustment for covariates including age, exposure noise level, and exposure time to noise.  As the Table 3 shown, there was a significant three-locus model (P=0.0107) including rs137852540, rs4880, and rs769214, with the highest level of testing accuracy (53.95%) and showed a better cross-validation consistency (6/10). Thus, our results suggested that rs769214 of CAT, rs4880 of SOD2 and rs137852540 of GJB2 gene, might account for the increased risks of NIHL in Chinese male workers in an interactive manner.

It is well known that genes involved in regulating the reactive oxygen species manganese-SOD2 and CAT could influence cochlea vulnerability to noise, because noise induces the release of free radicals and may damage the cochlear sensorial epithelium[8-9]. In the present study, our data firstly suggested that GJB2 polymorphisms might account for the NIHL in an interactive manner. Usually, the mutations of GJB2 are generally recognized as risks for the individuals with human hereditary hearing loss


Table 2. Logistic analysis for the associations between SNPs and NIHL

Genes and SNPs

Genotype

Individuals with normal hearing (n=456)

Individuals with NIHL (n=145)

OR (95%CI)

P Value*

CDH23

 

 

 

 

 

rs1227049

GG

220

62

1

 

GC+CC

236

83

1.00 (0.86-1.82)

0.25

rs3802711

CC

276

92

1

 

CT+TT

180

53

0.88 (0.60-1.30)

0.53

GSTP1

 

 

 

 

 

rs1695

AA

293

92

1

 

AG+GG

163

53

1.04 (0.70-1.53)

0.86

GJB2

 

 

 

 

 

rs137852540

AA

256

84

1

 

AG+GG

200

61

0.93 (0.64-1.36)

0.7

PMCA2

 

 

 

 

 

rs2289274

GG

234

74

1

 

GA+AA

222

71

1.01 (0.70-1.47)

0.95

SOD2

 

 

 

 

 

rs4880

TT

330

106

1

 

TC+CC

126

39

0.96 (0.63-1.47)

0.86

CAT

 

 

 

 

 

rs7943316

AA

223

57

1

 

AT+TT

233

88

1.48 (1.01-2.16)

0.04

rs769214

GG

223

57

1

 

GA+AA

233

88

1.48 (1.01-2.16)

0.04

Note. *Adjusted for gender, age, exposure noise level, and exposure time to noise.

Table 3. Best gene-Gene interaction models identified by the GMDR

Locus No.

Best combination

Cross-validation consistency

Testing accuracy

P value*

2

rs1227049, rs769214

4/10

0.5075

0.623

3

rs4880, rs137852540, rs769214

6/10

0.5395

0.0107

4

rs1227049, rs137852540, rs4880, rs769214

4/10

0.4891

0.9453

5

rs3802711, rs1695, rs137852540, rs2289274, rs769214

4/10

0.4858

0.623

6

rs3802711, rs1695, rs137852540, rs2289274, rs4880, rs769214

6/10

0.5118

0.1719

7

rs3802711, rs1227049, rs1695, rs137852540, rs2289274, rs4880, rs769214

9/10

0.4870

0.623

8

rs3802711, rs1227049, rs1695, rs137852540, rs2289274, rs4880, rs769214, rs7943316

10/10

0.4767

0.623

Note. *Adjusted for gender, age, exposure noise level, and exposure time to noise.


but not for the hearing loss induced by noise[10]. Therefore, more investigations should be performed to identify the interaction among susceptibility genes for the pathogenesis of NIHL in future.

The limitations of this study should be considered. Similar to the previous studies, our findings might not be generalizable to other populations because of the racial specificity. Moreover, the present sample size was modest, although the number of study participants met the requirement for analysis. Independent replications in larger Chinese workers occupationally exposed noise are required to confirm the role of the gene-gene interaction detected in present study for NIHL.

In conclusion, the significant associations were validated between two CAT polymorphisms and NIHL susceptibility in Chinese male workers occupationally exposed noise. Additionally, our results firstly indicated that significant gene-gene interactions among GJB2, SOD2, and CAT that might account for the NIHL development. In order to understand the questions behind the observed associations, further genetic and functional studies focused on identification of the underlying mechanism of NIHL should be performed in future.

#Correspondence should be addressed to CHEN Dong, Tel: 86-512-65880079, E-mail: cdong@suda.edu.cn; ZHANG Yong Hong, Tel: 86-512-65880079, E-mail: yhzhang @suda.edu.cn

Biographical note of the first author: WANG Sheng Li, male, born in 1975, PhD, majoring in Occupation Safety and Health.

Received: August 12, 2014;

Accepted: October 29, 2014

Reference

1.  Sliwinska-Kowalska M, Pawelczyk M. Contribution of genetic factors to noise-induced hearing loss: a human studies review. Mutat Res, 2013; 752, 61-5.

2.  Liu Y, Li X, Guo X, et al. SOD2 V16A SNP in the mitochondrial targeting sequence is associated with noise induced hearing loss in Chinese workers. Dis Markers, 2010; 28, 137-47.

3.  Fortunato G, Marciano E, Zarrilli F, et al. Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss. Clin Chem, 2004; 50, 2012-8.

4.  Shen H, Huo X, Liu K, et al. Genetic variation in GSTM1 is associated with susceptibility to noise-induced hearing loss in a Chinese population. J Occup Environ Med, 2012; 54, 1157-62.

5.  Van Eyken E, Van Laer L, Fransen E, et al. The contribution of GJB2 (Connexin 26) 35delG to age-related hearing impairment and noise-induced hearing loss. OtolNeurotol, 2007; 28, 970-5.

6.  Abreu-Silva R, Rincon D, Horimoto A, et al. The search of a genetic basis for noise-induced hearing loss (NIHL). Ann Hum Biol, 2011; 38, 210-8.

7.  Fortunato G, Marciano E, Zarrilli F, et al. Paraoxonase and superoxide dismutase gene polymorphisms and noise-induced hearing loss. Clin Chem, 2004; 50, 2012-8.

8.  Konings A, Van Laer L, Pawelczyk M, et al. Association between variations in CAT and noise-inducedhearingloss in twoindependent noise-exposed populations. Hum Mol Genet, 2007; 16, 1872-83.

9.  Carlsson P, Van Laer L, Borg E, et al. The influence of genetic variation inoxidative stress genes on human noise susceptibility. Hear Res, 2005; 202, 87-96.

10.Wei Q, Wang S, Yao J, et al. Genetic mutations of GJB2 and mitochondrial 12S rRNA in nonsyndromic hearing loss in Jiangsu Province of China. J Transl Med, 2013; 11, 163.


 

 
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