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XU Xiang Rong, WANG Jing Jing, YANG Qiu Yue, JIAO Jie, HE Li Hua, YU Shan Fa, GU Gui Zhen, CHEN Guo Shun, ZHOU Wen Hui, WU Hui, LI Yan Hong, ZHANG Huan Ling, ZHANG Zeng Rui, JIN Xian Ning. The Effect of PCDH15 Gene Variations on the Risk of Noise-induced Hearing Loss in a Chinese Population[J]. Biomedical and Environmental Sciences, 2017, 30(2): 143-146. doi: 10.3967/bes2017.019
Citation: XU Xiang Rong, WANG Jing Jing, YANG Qiu Yue, JIAO Jie, HE Li Hua, YU Shan Fa, GU Gui Zhen, CHEN Guo Shun, ZHOU Wen Hui, WU Hui, LI Yan Hong, ZHANG Huan Ling, ZHANG Zeng Rui, JIN Xian Ning. The Effect of PCDH15 Gene Variations on the Risk of Noise-induced Hearing Loss in a Chinese Population[J]. Biomedical and Environmental Sciences, 2017, 30(2): 143-146. doi: 10.3967/bes2017.019

The Effect of PCDH15 Gene Variations on the Risk of Noise-induced Hearing Loss in a Chinese Population

doi: 10.3967/bes2017.019
Funds:

the National Natural Science Foundation of China 81372940

research funds from the National Science and Technology Infrastructure Program of the People's Republic of China 2014BAI12B03

More Information
  • Author Bio:

    XU Xiang Rong, majoring in occupational health

    WANG Jing Jing, majoring in occupational health

  • Corresponding author: HE Li Hua, Tel: 13520831550 E-mail: Alihe2009@126.com; YU Shan Fa, yu-shanfa@163.com
  • Received Date: 2016-09-22
  • Accepted Date: 2017-01-01
  • Noise-induced hearing loss (NIHL) is a complex disease caused by interactions between environmental and genetic factors. This study investigated whether genetic variability in protocadherin related 15 (PCDH15) underlies an increased susceptibility to the development of NIHL in a Chinese population. The results showed that compared with the TT genotype of rs11004085, CT/CC genotypes were associated with an increased risk of NIHL [adjusted odds ratio (OR)=2.64; 95% confidence interval (CI): 1.14-6.11, P=0.024]. Additionally, significant interactions between the rs11004085 and rs978842 genetic variations and noise exposure were observed in the high-level exposure groups (P < 0.05). Furthermore, the risk haplotype TAGCC was observed when combined with higher levels of noise exposure (P < 0.05). Thus, our study confirms that genetic variations in PCDH15 modify the susceptibility to NIHL development in humans.
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  • [1] National Institute for Occupational Safety and Health (NIOSH). Noise and hearing loss prevention. 2013. http://www.cdc.gov/niosh/topics/noise/. [2013-7-11]
    [2] Basner M, Babisch W, Davis A, et al. Auditory and onauditory effects of noise on health. Lancet, 2014; 383, 1325-32. doi:  10.1016/S0140-6736(13)61613-X
    [3] National Health and Family Planning Commission of the People, s Republic of China. Briefing on the prevention of occupational diseases in 2013. [EB/OL]. http://www.nhfpc.gov.cn/jkj/s5899t/201406/ed8ed220d0b74010bcb6dcd8e340f4fb.shtml. [2016-6-30]
    [4] Ahmed ZM, Riazuddin S, Bernstein SL, et al. Mutations of The protocadherin gene PCDH15 cause Usher syndrome type 1F. Am J Hum Genet, 2001; 69, 25-34. doi:  10.1086/321277
    [5] Ahmed ZM, Riazuddin S, Ahmad J, et al. PCDH15 is Expressed in the neurosensory epithelium of the eye and ear and mutant alleles are Responsible for both USH1F and DFNB23. Hum Mol Genet, 2003; 12, 3215-23. doi:  10.1093/hmg/ddg358
    [6] Zheng QY, Yan D, Ouyang XM, et al. Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet, 2005; 14, 103-11. http://hmg.oxfordjournals.org/content/14/1/103.short
    [7] Konings A, Van Laer L, Wiktorek-Smagur A, et al. Candidate gene association study for noise-induced hearing loss in two independent noise-exposed populations. Ann Hum Genet, 2009; 73, 215-24. doi:  10.1111/ahg.2009.73.issue-2
    [8] Zhang X, Liu Y, Zhang L, et al. Genetic variations in protocadherin15 and their interactions with noise exposure associated with noise-induced hearing loss in Chinese population. Environ Res, 2014; 135, 247-52. doi:  10.1016/j.envres.2014.09.021
    [9] Xu XR, Yang QY, Jiao J, et al. Genetic variation in POU4F3 and GRHL2 associated with noise-induced hearing loss in Chinese population: A case-control study. Int J Environ Res Public Health, 2016; 13, 561. doi:  10.3390/ijerph13060561
    [10] Yang QY, Xu XR, Jie J, et al. Genetic variation in EYA4 on the risk of noise-induced hearing loss in Chinese steelworks firm sample. Occup Environ Med, 2016; 73, 823-8. http://oem.bmj.com/content/73/12/823.abstract
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The Effect of PCDH15 Gene Variations on the Risk of Noise-induced Hearing Loss in a Chinese Population

doi: 10.3967/bes2017.019
Funds:

the National Natural Science Foundation of China 81372940

research funds from the National Science and Technology Infrastructure Program of the People's Republic of China 2014BAI12B03

Abstract: Noise-induced hearing loss (NIHL) is a complex disease caused by interactions between environmental and genetic factors. This study investigated whether genetic variability in protocadherin related 15 (PCDH15) underlies an increased susceptibility to the development of NIHL in a Chinese population. The results showed that compared with the TT genotype of rs11004085, CT/CC genotypes were associated with an increased risk of NIHL [adjusted odds ratio (OR)=2.64; 95% confidence interval (CI): 1.14-6.11, P=0.024]. Additionally, significant interactions between the rs11004085 and rs978842 genetic variations and noise exposure were observed in the high-level exposure groups (P < 0.05). Furthermore, the risk haplotype TAGCC was observed when combined with higher levels of noise exposure (P < 0.05). Thus, our study confirms that genetic variations in PCDH15 modify the susceptibility to NIHL development in humans.

XU Xiang Rong, WANG Jing Jing, YANG Qiu Yue, JIAO Jie, HE Li Hua, YU Shan Fa, GU Gui Zhen, CHEN Guo Shun, ZHOU Wen Hui, WU Hui, LI Yan Hong, ZHANG Huan Ling, ZHANG Zeng Rui, JIN Xian Ning. The Effect of PCDH15 Gene Variations on the Risk of Noise-induced Hearing Loss in a Chinese Population[J]. Biomedical and Environmental Sciences, 2017, 30(2): 143-146. doi: 10.3967/bes2017.019
Citation: XU Xiang Rong, WANG Jing Jing, YANG Qiu Yue, JIAO Jie, HE Li Hua, YU Shan Fa, GU Gui Zhen, CHEN Guo Shun, ZHOU Wen Hui, WU Hui, LI Yan Hong, ZHANG Huan Ling, ZHANG Zeng Rui, JIN Xian Ning. The Effect of PCDH15 Gene Variations on the Risk of Noise-induced Hearing Loss in a Chinese Population[J]. Biomedical and Environmental Sciences, 2017, 30(2): 143-146. doi: 10.3967/bes2017.019
  • Noise-induced hearing loss (NIHL) is a major occupational health risk in industrialized countries worldwide that affects people of all ages, sex, and races. About 22-30 million US workers are exposed to hazardous noise levels at work and an estimated US $242 million is spent annually on compensation for disability associated with hearing loss[1-2]. Data from the Centers for Disease Control and Prevention (China) showed that NIHL is the third most serious occupational disease in China[3]. NIHL not only affects workers' health, but also causes social isolation, impaired communication, and decreased productivity.

    NIHL is a complex form of hearing loss induced by interactions between genetic and environmental factors. Noise is the most studied environmental factor associated with hearing loss; it is harmful over 85 dB and causes both mechanical and metabolic damage. However, not all workers develop NIHL after exposure to identical noise levels. Thus, genetic factors might also influence the susceptibility to NIHL.

    PCDH15 is a member of the cadherin superfamily of calcium-dependent cell-cell adhesion molecules[4], which is localized in the inner ear hair cell stereocilia and retinal photoreceptors. Mutations in PCDH15 have been associated with both non-syndromic (DFNB23) and syndromic hearing loss (Usher syndrome type1F, USH1F)[5-6]. In 2009, research in Swedish and Polish populations first reported that single nucleotide polymorphisms (SNPs) in PCDH15 were associated with NIHL risk[7]. Even though the reported variation is relatively common in certain European populations, racial differences need to be considered. Zhang et al. were the first to conduct research on this topic in China, reporting that the rs11004085 genetic variation in PCDH15 was associated with NIHL[8]. However, the findings in this study were restricted to men living in South China; thus, more studies in other independent samples are necessary to confirm these findings. Therefore, this study investigated whether susceptibility to NIHL was associated with PCDH15 genetic variations in a northern Chinese population.

    This study included 6, 309 workers exposed to continuous and steady occupational noise in a steel factory in Henan province, China. A detailed description of the inclusion and exclusion criteria can be found elsewhere[9-10]. The case group was defined as those individuals with an average high-frequency (3, 4, and 6 kHz) binaural hearing level (HL)≥40 dB. The individually matched control group was defined as binaural HL of any frequency (0.5, 1, 2, 3, 4, and 6 kHz) < 25 dB. Finally, 344 matched pairs of participants were recruited from the steel factory cohort from September to December in 2013 and September to November in 2014. The study was approved by the Ethics Committee of the Henan Institute of Occupational Medicine.

    All the subjects answered a structured questionnaire and underwent physical examinations by trained physicians. Noise exposure levels were assessed during their working time, which was evaluated with equivalent continuous dB (A)-weighted sound pressure levels (LAeq, 8h). Cumulative noise exposure (CNE) was calculated to determine the actual noise exposure for each subject[9-10].

    A total of 12 candidate SNPs were selected based on the inclusion criteria[9-10], including rs10825112, rs10825113, rs1900443, rs12258253, rs2135720, rs11004085, rs11004142, rs996320, rs7081730, rs978842, rs11004439, and rs7922254. The genotypes were determined using the commercial SNPscanTM multiplex SNP genotyping kit (Genesky Biopharm Technology Co., Ltd, Shanghai, China).

    Hardy-Weinberg equilibrium (HWE) was checked for each SNP in the control subjects using χ2-tests. Paired samples t-tests were used to compare demographic information for continuous variables, while χ2-tests were used for categorical variables. Adjusted ORs with 95% CIs were computed by conditional logistic regression analysis to test for associations between NIHL risk and the genotypes. Bonferroni correction was performed to control for multiple testing, which resulted in a corrected significance level of 0.004 (P=0.05/12=0.004). Haploview was used to estimate the haplotypes and investigate the linkage disequilibrium (LD) between the SNPs. All statistical analyses were two-sided and performed using IBM SPSS Statistics for Windows, Version 20.0, with a significance level of 0.05.

    The basic characteristics of the subjects are shown in Table S1 (www.besjournal.com). The average binaural HL of high frequency noise exposure in the case group was significantly higher than that of the control subjects (P=0.024). The percentage of smokers was also higher in the case group (P < 0.001). The two groups appeared to be well matched by age, gender, body mass index (BMI), hypertension, drinking status, exposure time, the use of earplug, noise exposure level, and CNE (P > 0.05).

    Variables Case (n=344) Control (n=344) P
    Age (y), mean±SD 40.7±8.4 40.1±8.4 0.998
    Tenure (y), mean±SD 19.1±9.2 18.6±9.0 0.747
    HLa, mean±SD 51.1±8.9 10.2±8.6 0.024
    BMIb, mean±SD 25.5±3.4 25.3±3.4 0.964
    Gender, n (%)
        male 327 (95.1) 327 (95.1) 1.000
        female 17 (4.9) 17 (4.9)
    Hypertension, n (%)
        yes 140 (40.7) 142 (41.3) 0.877
        no 204 (59.3) 202 (58.7)
    Smoking, n (%)
        yes 217 (63.1) 172 (50.0) < 0.001
        no 127 (36.9) 172 (50.0)
    Drinking (Alcohol), n (%)
        yes 233 (71.6) 228 (69.0) 0.685
        no 111 (28.4) 116 (31.0)
    Protector (Earplug), n (%)
        yes 140 (40.7) 148 (43.0) 0.536
        no 204 (59.3) 196 (57.0)
        Noise exposure level, dB (A) 85.7±3.9 85.7±3.7 0.152
        CNEc, dB (A) 97.9±4.6 97.9±4.4 0.152
    Note. aHL: hearing level in high frequency; bBMI (Body Mass Index) was calculated as body weight (kg)/height (m)2; cCNE: cumulative noise exposure.

    Table Table S1.  Basic Characteris cs of Case and Control Subjects

    The distributions of the PCDH15 genotypes and alleles in the case and control subjects are shown in Table 1. Of the 12 SNPs, only one significant association of genotype rs11004085 was observed between the two groups (P=0.039). As shown in Table S2 (www.besjournal.com), for rs11004085, after adjusting for BMI, smoking, drinking, and CNE, the frequencies of the CT compared with the TT genotype in the case group was significantly higher than that in the control group (adjusted OR=3.03; 95% CI: 1.26-7.33, P=0.014). Compared with subjects carrying the TT genotype, subjects with CT/CC genotypes were at increased risk of NIHL (adjusted OR=2.64; 95% CI: 1.14-6.11, P=0.024). Thus, this SNP genotype (CT/CC on rs11004085) was identified as a risk factor associated with NIHL. These findings were in agreement with two previously published studies of Polish and Swedish populations and a southern Chinese population[7-8]. Mutations on rs11004085 might decrease calcium binding capacity, weaken its interaction with other genes such as CDH23, and affect its adhesion function, which increase the stereocilia bundle susceptibility to noise injury[4-6]. However, no significant differences between two groups in terms of the distribution of genotypes or alleles of the other 11 SNPs were found in our study, as shown in Table S3 (www.besjournal.com). Similarly, no significant differences were detected when Zhang and colleagues compared allele and genotype frequencies for the SNPs on rs12258253[8]. This SNP did not seem to play an important role in NIHL in the Chinese population, although more studies are needed to confirm these findings.

    SNPs Minor/major
    Allele (A1/A2)
    Loca on Minor Allele Frequency P (H-W)a A1A1/A1A2/A2A2 Pb
    HapMap-CHB Case Control Case Control
    rs10825112 C/A 3'UTR 0.057 0.071 0.078 0.693 0/49/295 3/48/293 0.537
    rs10825113 A/G intron32 0.146 0.214 0.201 0.116 17/113/212 19/100/225 0.593
    rs1900443 T/C intron27 0.306 0.259 0.230 1.000 22/134/185 18/122/204 0.251
    rs12258253 C/T intron25 0.278 0.243 0.219 0.509 22/123/197 14/123/204 0.479
    rs2135720 G/A exon20 0.427 0.507 0.480 0.792 89/171/82 78/174/89 0.335
    rs11004085 C/T intron16 0.023 0.061 0.030 0.129 0/21/323 1/8/333 0.039
    rs11004142 C/A intron9 0.159 0.156 0.153 0.504 9/89/246 10/85/249 0.957
    rs996320 A/G intron9 0.159 0.177 0.154 0.328 14/94/236 11/84/247 0.364
    rs7081730 T/C intron8 0.232 0.195 0.170 0.085 18/98/228 15/87/242 0.312
    rs978842 C/T intron7 0.222 0.193 0.235 0.550 15/103/225 18/126/200 0.118
    Note. aHWE test was performed using χ2 test for each SNP among control subjects; bAdjusted for BMI, drinking, smoking, and CNE.

    Table 1.  Distri ons of PCDH15 Alleles and Genotypes in the Case and Control Subjects

    Genotypes Case Control OR (95% CI)a Pa
    N % N %
    rs11004085
    TT 323 94.2 333 97.7 1.00
    CT 21 5.8 8 2.0 3.03 (1.26-7.33) 0.014
    CC 0 0.0 1 0.3 - 0.978
    CC/CT 21 5.8 8 2.3 2.64 (1.14-6.11) 0.024
    T Allele 667 96.9 674 98.0 1.00
    C Allele 21 3.1 10 1.5 - 0.978
    Note. aAdjusted for BMI, drinking, smoking and CNE.

    Table Table S2.  Single SNP Analysis of Association of rs11004085 with the Risk of NIHL

    SNPs Genotypes Case Control OR (95% CI)* P*
    N % N %
    rs10825112 AA 295 85.8 293 85.2 1.00
    CA 49 14.2 48 14.0 0.10 (0.63-1.56) 0.985
    CC 0 0.0 3 0.9 0.975
    CA/CC 49 14.2 51 14.8 0.93 (0.60-1.45) 0.741
    A allele 639 92.9 634 92.2 1.00
    C allele 49 7.1 54 7.8 0.92 (0.59-1.43) 0.715
    rs10825113 GG 212 61.6 225 65.4 1.00
    GA 113 32.8 100 29.1 1.19 (0.85-1.67) 0.307
    AA 17 4.9 19 5.5 0.93 (0.48-1.83) 0.840
    GA/AA 130 37.8 119 34.6 1.15 (0.83-1.58) 0.398
    GG/GA 325 94.5 325 94.5 1.00
    AA 17 4.9 19 5.5 0.88 (0.45-1.71) 0.706
    G allele 537 78.1 550 79.9 1.00
    A allele 147 21.4 138 20.1 0.88 (0.45-1.71) 0.703
    rs1900443 CC 185 53.8 204 59.3 1.00
    TC 134 39.0 122 35.5 1.19 (0.86-1.63) 0.293
    TT 22 6.4 18 5.2 1.26 (0.66-2.40) 0.485
    TC/TT 156 45.3 140 40.7 1.19 (0.88-1.60) 0.268
    CC/TC 319 92.7 326 94.8 1.00
    TT 22 6.4 18 5.2 1.19 (0.63-2.24) 0.599
    C allele 504 73.3 530 77.0 1.00
    T allele 178 25.9 158 23.0 1.20 (0.89-1.61) 0.243
    rs12258253 TT 197 57.3 204 59.3 1.00
    TC 123 35.8 123 35.8 0.99 (0.72-1.37) 0.955
    CC 22 6.4 14 4.1 1.50 (0.76-2.99) 0.245
    TC/CC 145 42.2 137 39.8 1.06 (0.78-1.44) 0.710
    TT/TC 320 93.0 327 95.1 1.00
    CC 22 6.4 14 4.1 1.51 (0.76-2.98) 0.238
    T allele 517 75.1 531 77.2 1.00
    C allele 167 24.3 151 21.9 1.50 (0.76-2.96) 0.243
    rs2135720 CC 82 23.8 89 25.9 1.00
    TC 171 49.7 174 50.6 0.85 (0.59-1.22) 0.380
    TT 89 25.9 78 22.7 0.81 (0.52-1.27) 0.353
    TC/TT 260 75.6 252 73.3 0.84 (0.60-1.18) 0.319
    CC/TC 253 73.5 263 76.5 1.00
    TT 89 25.9 78 22.7 0.90 (0.62-1.31) 0.592
    C allele 335 48.7 352 51.2 1.00
    T allele 349 50.7 330 48.0 1.20 (0.85-1.70) 0.297
    rs11004142 AA 246 71.5 249 72.4 1.00
    CA 89 25.9 85 24.7 1.01 (0.70-1.45) 0.953
    CC 9 2.6 10 2.9 0.92 (0.34-2.44) 0.861
    CA/CC 98 28.5 95 27.6 1.00 (0.71-1.41) 1.000
    AA/CA 335 97.4 334 97.1 1.00
    CC 9 2.6 10 2.9 0.92 (0.34-2.44) 0.859
    A allele 581 84.4 583 84.7 1.00
    C allele 107 15.6 105 15.3 1.01 (0.71-1.42) 0.977
    rs996320 GG 236 68.6 247 71.8 1.00
    GA 94 27.3 84 24.4 1.11 (0.78-1.58) 0.558
    AA 14 4.1 11 3.2 1.41 (0.60-3.31) 0.426
    GA/AA 108 31.4 95 27.6 1.14 (0.82-1.60) 0.436
    GG/GA 330 95.9 331 96.2 1.00
    AA 14 4.1 11 3.2 1.37 (0.59-3.20) 0.461
    G allele 566 82.3 578 84.0 1.00
    A allele 122 17.7 106 15.4 1.41 (0.61-3.30) 0.423
    rs7081730 CC 228 66.3 242 70.3 1.00
    TC 98 28.5 87 25.3 1.14 (0.81-1.60) 0.467
    TT 18 5.2 15 4.4 1.37 (0.65-2.86) 0.406
    TC/TT 116 33.7 102 29.7 1.16 (0.84-1.61) 0.369
    CC/TC 326 94.8 329 95.6 1.00
    TT 18 5.2 15 4.4 1.30 (0.63-2.69) 0.476
    C allele 554 80.5 571 83.0 1.00
    T allele 134 19.5 117 17.0 1.15 (0.83-1.60) 0.391
    rs978842 TT 225 65.4 200 58.1 1.00
    TC 103 29.9 126 36.6 1.25 (0.90-1.72) 0.184
    CC 15 4.4 18 5.2 1.47 (0.70-3.09) 0.305
    TC/CC 118 34.3 144 41.9 1.29 (0.94-1.76) 0.113
    TT/TC 328 95.3 326 94.8 1.00
    CC 15 4.4 18 5.2 1.37 (0.66-2.83) 0.403
    T allele 553 80.4 526 76.5 1.00
    C allele 133 19.3 162 23.5 1.34 (0.65-2.77) 0.427
    rs11004439 AA 243 70.6 241 70.1 1.00
    CA 89 25.9 98 28.5 0.94 (0.66-1.34) 0.736
    CC 12 3.5 5 1.5 2.43 (0.83-7.12) 0.105
    CA/CC 101 29.4 103 29.9 1.01 (0.72-1.43) 0.946
    AA/CA 332 96.5 339 98.5 1.00
    CC 12 3.5 5 1.5 2.49 (0.86-7.23) 0.094
    A allele 575 83.6 580 84.3 1.00
    C allele 113 16.4 108 15.7 1.01 (0.72-1.42) 0.953
    rs7922254 AA 204 59.3 189 54.9 1.00
    TA 117 34.0 139 40.4 0.90 (0.57-1.12) 0.187
    TT 23 6.7 16 4.7 1.41 (0.72-2.76) 0.323
    TA/TT 140 40.7 155 45.1 0.86 (0.63-1.19) 0.359
    AA/TA 321 93.3 328 95.3 1.00
    TT 23 6.7 16 4.7 1.55 (0.81-3.00) 0.189
    A allele 525 76.3 517 75.1 1.00
    T allele 163 23.7 171 24.9 0.86 (0.63-1.18) 0.353
    Note. *Adjusted for BMI, smoking, drinking, and CNE.

    Table Table S3.  Associations of Candidate SNPs with the Risk of NIHL

    As noise is the most common cause of NIHL, stratified analysis by noise exposure level or CNE was conducted, the results of which are shown in Table 2. For rs11004085, compared with the TT genotype, CT/TT genotypes resulted in an increased risk of NIHL for noise exposure levels > 85 dB (A) (adjusted OR=4.61; 95% CI: 1.25-17.04, P=0.022); for CNE > 95 dB (A), the CT/TT genotypes were also at increased risk (P=0.011), with adjusted OR of 5.26 and 95% CI of 1.47-18.79. For rs978842, no overall significant associations with NIHL were observed before stratification. Compared to those with TT genotypes, noise exposure levels > 85 dB (A) were associated with an increased risk for NIHL among subjects carrying TC/CC genotypes (adjusted OR=1.58; 95% CI: 1.03-2.42, P=0.035). Therefore, this study iden fied significant SNP-environment interac ons between two SNPs, rs11004085 and rs978842, and noise exposure, a finding concordant with that of previous research[8]. It is not surprising that NIHL is posi vely correlated with noise exposure, as workers are more susce ble to NIHL when exposed to greater noise exposure levels. Taken together, these data suggest that the interac ons between PCDH15 polymorphisms and noise exposure might play important roles in the incidence of NIHL.

    Variables SNPs Case Control OR (95% CI)a Pa
    Genetype N (%) Genetype N (%)
    Noise exposure level [dB (A)]
        ≤85 rs11004085 TT 151 (93.8) TT 144 (96.6) 1.00 0.212
    CT/CC 10 (6.2) CT/CC 5 (3.4) 2.03 (0.67-6.19)
         > 85 TT 172 (94.0) TT 190 (98.4) 1.00 0.022
    CT/CC 11 (6.0) CT/CC 3 (1.6) 4.61 (1.25-17.04)
        ≤85 rs978842 TT 94 (58.4) TT 94 (63.1) 1.00 0.457
    TC/CC 67 (41.6) TC/CC 55 (36.9) 1.19 (0.75-1.91)
         > 85 TT 106 (57.9) TT 131 (68.2) 1.00 0.035
    TC/CC 77 (42.1) TC/CC 61 (31.8) 1.58 (1.03-2.42)
    CNE [dB (A)]
        ≤95 rs11004085 TT 85 (92.4) TT 85 (93.4) 1.00 0.523
    CT/CC 7 (66.6) CT/CC 6 (6.6) 1.47 (0.45-4.73)
         > 95 TT 238 (94.4) TT 250 (98.8) 1.00 0.011
    CT/CC 14 (5.6) CT/CC 3 (1.2) 5.26 (1.47-18.79)
    Note. aAdjusted for BMI, drinking, smoking, and CNE.

    Table 2.  Strafied Analysis of PCDH15 by Noise Exposure Level or CNE

    In order to ide fy true associa ons that might be missed because of the incomplete informa on provided by the individual SNP, we primarily applied a haplotype-centric approach, taking into account different levels of noise exposure, to test for interac ons. The pairwise LD between the 12 SNPs is shown in Table S4 (www.besjournal.com). From Table 3, no significant P-values were obtained before stra fica on (P > 0.05). When noise exposure level > 85 dB (A) were compared with haplotype TAGCT, the frequencies of haplotype TAGCC was significantly higher in the case group (adjusted OR=1.84; 95% CI=1.01-3.33, P < 0.05); for CNE > 95 dB (A), subjects with haplotype TAGCC were more susceptible to NIHL (adjusted OR=1.79; 95% CI=1.08-2.95, P < 0.05), indicating it to be a risk haplotype. Our finding was concordant with that of a previous study[8], suggesting that multiple genetic variations in PCDH15 modify NIHL risk and that higher noise exposure might increase risk.

    SNPs rs10825112 rs10825113 rs1900443 rs12258253 rs2135720 rs11004085 rs11004142 rs996320 rs7081730 rs978842 rs11004439 rs7922254
    rs10825112 0.728 0.046 0.013 0.704 0.443 0.134 0.182 0.207 0 0 0
    rs10825113 0.124 0.593 0.472 0.601 0.174 0.06 0.071 0.047 0.062 0 0
    rs1900443 0.001 0.283 0.919 0.289 0.47 0.126 0.146 0.109 0.073 0 0
    rs12258253 0 0.191 0.795 0.211 0.495 0.121 0.148 0.121 0.095 0 0
    rs2135720 0.041 0.095 0.027 0.014 0.616 0.021 0.003 0.028 0.017 0 0
    rs11004085 0.056 0.003 0.016 0.019 0.009 0.431 0.729 0.953 0.899 0 0
    rs11004142 0.008 0.003 0.009 0.009 0 0.023 0.925 0.843 0.541 0.275 0
    rs996320 0.013 0.004 0.013 0.015 0 0.062 0.784 0.923 0.644 0.094 0
    rs7081730 0.015 0.002 0.008 0.011 0 0.094 0.58 0.758 0.689 0.235 0
    rs978842 0 0.004 0.005 0.008 0 0.068 0.195 0.302 0.388 0.176 0.23
    rs11004439 0 0 0 0 0 0 0.003 0 0 0.002 0.907
    rs7922254 0 0 0 0 0 0 0 0 0 0.002 0.492
    Note. The upper triangle was D' value and the lower triangle was r2 value.

    Table Table S4.  Linkage Disequilibrium test of PCDH15 Gene

    Haplotypea, b Case
    (n, %)
    Control
    (n, %)
    Adjusted OR (95% CI)c
    Total Noise Exposure
    Level≤85 dB (A)
    Noise Exposure
    Level > 85 dB (A)
    CNE≤95 dB (A) CNE > 95 dB (A)
    TAGCT 479 (69.6) 516 (75.0) 1.00 1.00 1.00 1.00 1.00
    TCATC 59 (8.6) 61 (8.9) 1.03 (0.70-1.51) 1.27 (0.72-2.24) 0.87 (0.51-1.47) 1.08 (0.53-2.18) 1.03 (0.65-1.63)
    TAGCC 59 (8.6) 42 (6.1) 1.51 (1.00-2.30) 1.32 (0.72-2.41) 1.84 (1.01-3.33)d 1.13 (0.52-2.46) 1.79 (1.08-2.95)d
    TCATT 23 (3.3) 25 (3.5) 0.94 (0.52-1.69) 1.48 (0.58-3.79) 0.68 (0.32-1.47) 3.55 (0.72-17.58) 0.72 (0.37-1.34)
    Note. aHaplotype analysis was restricted to the SNPs that were in one block (D' > 0.4); bHaplotypes of PCDH15 were deduced for the following SNPs: rs11004085, rs11004142, rs996320, rs7081730, and rs978842; cAdjusted for BMI, smoking and drinking; only haplotype with frequency > 3% was shown in this table; dBold signifies P < 0.05.

    Table 3.  Assessment of the Associations between Haplotypes and NIHL

    However, after applying Bonferroni correction, the associations were no longer statistically significant.

    These findings are of value for the prevention of NIHL. People with the CT/CC rs11004085 genotype or the TAGCC PCDH15 risk haplotype should take care to avoid high levels of noise exposure in their workplaces.

    The limitations of this study should be acknowledged when interpreting the results. Firstly, although some workers might be exposed to community noise, such as sleeping with the television on and listening to music with headphones, these factors were too complicated to consider in the current study. Secondly, while this study identified TAGCT as a potential risk haplotype, the molecular mechanism are not clear and further functional studies are warranted.

    In conclusion, our findings indicated that genetic variations in PCDH15 may play an important role in genetic susceptibility to NIHL. The effect of gene-environment interactions and multiple loci on the development of NIHL were detected. However, after Bonferroni correction, these differences were not found to be significant. Further studies involving a larger number of individuals and independent populations are required to assess these findings.

Reference (10)

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